Butenoic or propenoic acid derivative

ABSTRACT

A butenoic or propenoic acid derivative having the following formula in which G is an aryl or a heterocyclic ring, R11 and R12 are hydroben or an alkyl, X is sulfur or oxygen, R2 and R3 are hydrogen, an substituent such as an alkyl and J is pyridyl or phenyl having substituents and a heterocyclic ring may be formed between R2, R3 and J is provided here and is useful in the pharmacological field. ##STR1##

This application is a a divisional of copending application Ser. No.07/354,306 filed on May 19, 1989 now U.S. Pat. No. 5,047,417.

The invention relates to a butenoic or propenoic acid derivative havingphenyl or a heterocyclic ring at its omega position. It is useful as adrug, in particular having an excellent coronary vasodilating and heartrate lowering effect.

PRIOR ART

In countries of Europe and America, cardiovascular diseases head thelist of death causes. In Japan, although cerebrovascular diseases suchas cerebral apoplexy ranked high in the list of the death causes,ischemic heart disease has prominently increased recently, as thelife-style and eating habit cf Japanese have neared those of Europeanand American.

Ischemic heart disease generally refers to a series of heart diseasescaused when the supply of oxygen to cardiac muscle cannot make up formyocardial oxygen consumption. Representative examples thereof includecoronary sclerosis, acute cardiac infarction and angina pectoris.Although nitro drugs, calcium antagonists and 8-blockers are nowgenerally used for the treatment of these diseases, no decisivelyeffective drug has been found as yet, so that it is highly expected todevelop a novel drug more excellent than those of the prior art.

SUMMARY OF THE INVENTION

Under these circumstances, the inventors of the present invention haveattempted to develop a new type of a remedy for ischemic heart disease.Particularly, the inventors have long studied to find out a compoundwhich exhibits excellent coronary vasodilating and heart rate loweringeffects.

The invention provides a butenoic or propenoic acid derivative havingthe formula (II) and a pharmacologically accepatable salt thereof:##STR2## which is defined by each of the following definitions (I), (II)and (III):

(I) having the formula (I) in which in the formula (II) G is R1-phenyl,R11 and R12 each are hydrogen, m is one and X is oxygen, ##STR3##wherein R1 is a hetero-aryl group, R2 and R3 each are hydrogen, a loweralkyl, a cycloalkyl or an allyl group, or R2 and R3 may form a 5- to7-membered saturated heterocyclic ring together with the nitrogen atomto which they are bonded, A is an alkylene group having 1 to 6 carbonatoms, which alkylene may have a lower alkyl, a lower alkoxy or hydroxy,J is pyridyl or a phenyl having substituents R4, R5 and R6: ##STR4##which R4, R5 and R6 each are hydrogen, a halogen atom, a lower alkyl, alower alkoxy, hydroxy, nitro, cyano, trifluromethyl, analkylsulfonyloxy, --NR7R8, R7 and R8 being hydrogen or a lower alkyl, oran alkanoylamino, or two of R4, R5 and R6 may form an alkylenedioxytogether with two adjacent carbon atoms on the phenyl, or R4, R5 and R6may form a 5- to 7-membered ring together with the --(CH2)--, and n isan integer of from 1 to 6;

(II) having the formula (II) in which: G is naphthyl or a phenyl havingsubstituents R15 and R16: ##STR5## R15 and R16 being hydrogen, a loweralkyl, a lower alkoxy, a halogen, --NR7R8, R7 and R8 being hydrogen or alower alkyl, cyano, trifluromethyl, an alkanoylamino, trifluoroalkoxy,an alkylsulfonyl, nitro, hydroxyl, an alkylthio, an alkylsulfonylamino,an alkylcarbonylamino or a carbamoyl, or R15 and R16 may form a cyclicring together with oxygen between two adjacent carbon atoms, R11 and R12each are hydrogen, cyano, a lower alkyl, or a halogen or they may form acyclic ring together with oxygen and the carbon on the phenyl, m is zeroor 1, X is oxygen or sulfur, R2 and R3 each are hydrogen, a lower alkyl,a lower alkoxy, a cycloalkyl, a trifluoroalkyl or a lower alkenyl, or R2and R3 may form a 5- to 7-membered saturated heterocyclic ring togetherwith the nitrogen atom to which they are bonded, or R2 may form a ringtogether with R12, or R3 may form a ring having a nitrogen atom togetherwith the --(CH2)n--, R2 may form a 5- to 7-membered saturatedheterocylic ring together with A, R3 may form a 5- to 7-memberedsaturated heterocyclic ring together with A, A is an alkylene grouphaving 1 to 6 carbon atoms, which alkylene may have a lower alkyl group,n is an integer of 1 to 6, J is pyridyl or a phenyl having substituentsR4, R5 and R6: ##STR6## which R4, R5 and R6 each are hydrogen, a halogenatom, a lower alkyl, a lower alkoxy, hydroxy, nitro, trifluromethyl, analkylsulfonyloxy, --NR7R8, R7 and R8 being hydrogen or a lower alkyl, oran alkanoylamyl, or two of R4, R5 and R6 may form an alkylenedioxytogether with two adjacent carbon atoms on the phenyl, or J may form acyclic ring having a nitrogen together with the group --(CH2)n--; and

(III) having the formula (III) in which in the formula (II) R11 and R12are hydrogen, X is oxygen, ##STR7## wherein R31 is a hetero-aryl group,R2 and R3 each are hydrogen, a lower alkyl, a cycloalkyl or allyl, or R3may form a 5- to 7-membered saturated heterocyclic ring together withthe nitrogen and the --(CH2)n--, or R3 may form a 5- to 7-memberedcyclic heteroring having nitrogen or nitrogen and oxygen together with Aand the nitrogen, A is an alkylene having 1 to 3 carbon atoms which mayhave a lower alkyl, hydroxy or a lower alkoxy group, W is oxygen,sulfur, vinylene (--C═C--) or azomethyne (--N═CH--), J is pyridyl or aphenyl having substituents R4, R5 and R6, which is hydrogen, a halogen,a lower alkyl, a lower alkoxy, hydroxy, nitro, cyano, trifluromethyl, analkylsulfonyloxy, --NR7R8, R7 and R8 being hydrogen or a lower alkylgroup, or an alkanoylamino, or two of R4, R5 and R6 may form analkylenedioxy together with two adjacent carbon atoms on the phenyl, oneof R4, R5 and R6 may form a 5- to 7-membered cyclic ring together withthe group --(CH2)n--, n is an integer of 1 to 6, --(CH2)n-- may have alower alkyl.

When one of R4, R5 and R6 forms a ring with --(CH2)n--, the followingare preferable: ##STR8##

In the above shown definitions I, II and III, two or more symbols aredefined independently of each other when they are defined at the sametime. Namely they may have either the same definitions as each other ordifferent definitions from each other.

The pharmacologically acceptable salt according to the present inventionincludes inorganic acid salts such as hydrochloride, sulfate,hydrobromide and phosphate and organic acid salts such as formate,acetate, trifluoroacetate, maleate, fumarate, tartrate,methanesulfonate, benzenesulfonate and toluenesulfonate.

Although the compound of the present invention has an asymmetric carbonatom depending upon the kind of a substituent to be present as opticalisomers, it is a matter of course that these optical isomers fall withinthe scope of the present invention.

The compound of the invention includes the three groups of itsembodiments, (I), (II) and (III):

(I) a 4-phenyl-3-butenoic acid derivative having the formula (I) and thedefinition (I) and a pharmacologically acceptable salt thereof;

(II) a butenoic or propionic acid derivative having the formula (II) andthe definition (II) and a pharmacologically acceptable salt thereof; and

(III) a 4-aryl-3-butenoic acid derivative having the formula (III) andthe definition (III) and a pharmacologically acceptable salt thereof.

The compound of the invention will be described below more in detail inreference to the embodiments (I), (II) and (III).

EMBODIMENT (I)

The inventors of the present invention have long studied to find out acompound satisfying the above object and have found that a 4-phenyl-3butenoic acid derivative represented by the general formula (I) canattain the above object

Namely, the present invention relates to a 4-phenyl-3-butenoic acidderivative represented by the following general formula or apharmacologically acceptable salt thereof: ##STR9## wherein R¹ standsfor a hetero-aryl group, R² and R³, which may be the same or different,each stand for a hydrogen atom, a lower alkyl group, a cycloalkyl groupor an allyl group, or R² and R³ form a 5- to 7-membered saturatedheterocyclic ring together with the nitrogen atom to which they arebonded, A stands for an alkylene group having 1 to 6 carbon atoms, withthe proviso that a lower alkyl group may be bonded to any carbon of thealkylene group, J stands for a group ##STR10## {in which R⁴, R⁵ and R⁶which may be the same or different, each stand for a hydrogen atom, ahalogen atom, a lower alkyl group, a lower alkoxy group, a hydroxylgroup, a nitro group, a cyano group, a trifluoromethyl group, analkylsulfonyloxy group, a group ##STR11## (in which R⁷ and R⁸, which maybe the same or different, each stand for a hydrogen atom or a loweralkyl group) or an alkanoylamino group, and two of R⁴, R⁵ and R⁶ mayform an alkylene-dioxy group between adjacent carbon atoms or R4, R5 orR6 may form a 5- to 7-membered ring together with the group --(CH2)n--)or a pyridyl group, and n is an integer of 1 to 6.

It is preferable that R1 is imidazolyl such as 1-imidazolyl or pyrrolylsuch as 1-pyrrolyl and 3-pyrrolyl and n is an integer of 1 to 3.

It is also preferable that J is the phenyl having a substituent(s) suchas m,p-dimethoxyphenyl, m-dimethoxyphenyl and m,m,p-trimethoxyphenyl, R4is a lower alkoxy, R5 is a lower alkoxy and R6 is hydrogen.

It is preferable that R1 is an imidazoyl, R2 is hydrogen, R3 is methyl,J is the phenyl having a substituent(s) and R4, R5 and R6 each arehydrogen or a lower alkoxy.

It is preferable that R1 is an imidazolyl, R2 is hydrogen, R3 is methyland J is m,p-dimethoxyphenyl.

The lower alkyl group defined with respect to R², R³, R⁴, R⁵, R⁶, R⁷ andR⁸ in formula (I) stands for a straight-chain or branched alkyl grouphaving 1 to 6 carbon atoms and examples thereof include methyl, ethyl,n-propyl, n-butyl, isopropyl, isobutyl, 1-methylpropyl, tert-butyl,n-pentyl, 1-ethylpropyl isoamyl and n-hexyl groups, among which methyland ethyl groups are most preferred.

The lower alkoxy group defined with respect to R⁴, R⁵ and R⁶ stands foran alkoxy group derived from a lower alkyl group defined above.

The cycloalkyl group defined with respect to R² and R³ stands for a 3-to 6-membered cycloalkyl group and preferred examples thereof includecyclopentyl and cyclohexyl groups.

The hetero-aryl group defined with respect to R¹ stands for asubstituted or unsubstituted heterocyclic group, the heterocyclic ringof which may contain one or more nitrogen, oxygen or sulfur atoms.Examples thereof include imidazolyl groups such as 1-imidazolyl and2-imidazolyl groups; pyridyl groups such as 3-pyridyl and 4-pyridylgroups; pyrrolyl groups such as 1-pyrrolyl and 3-pyrrolyl groups;nitrogenous hetero-aryl groups such as pyrazolyl, indolyl, indazolyl,isoquinolyl, quinolyl, quinoxalinyl, quinazolinyl and imidazopyridylgroups and hetero-aryl groups containing not only a nitrogen atom butalso an oxygen atom such as oxazolyl and isoxazolyl groups, among which1-imidazolyl group is most preferred.

Alternatively, the hetero-aryl group may be substituted with a loweralkyl group such as a methyl group.

When R² and R³ form a 5- to 7-membered saturated heterocyclic ringtogether with the nitrogen atom to which they are bonded, the grouprepresented by the formula ##STR12## is, for example, a grouprepresented by the formula: ##STR13##

The alkylsulfonyloxy group defined with respect to R⁴, R⁵ and R⁶ may beone derived from a lower alkyl group described above, while thealkanoylamino group may be one derived from a lower alkyl groupdescribed above.

A stands for an alkylene group having 1 to 6 carbon atoms, preferablyone having about 3 carbon atoms. The alkylene group may have an alkylgroup such as a methyl group bonded to any carbon atom thereof.

J stands for a group represented by the formula: ##STR14## (wherein R⁴,R⁵ and R⁶ are each as defined above) or a pyridyl group. It ispreferable that R⁴, R⁵ and R⁶ are each a lower alkoxy group having 1 to3 carbon atoms, still preferably a methoxy group. The pyridyl groupincludes 2-pyridyl, 3-pyridyl and 4-pyridyl groups.

Preferable compounds are: ##STR15##

Representative processes for the preparation of the compounds of thepresent invention will now be described.

PREPARATION PROCESS ##STR16## wherein R¹, R², R³, n, A and J are each asdefined above.

Namely, the objective compound (I) can be prepared by reacting acarboxylic acid represented by the general formula (II) or a reactivederivative thereof with an amine compound represented by the generalformula (III) to carry out amidation.

The reactive derivative of the compound (II) includes acyl halides suchas acyl chloride and acyl bromide; acid azides; reactive esters thereofwith N-hydroxybenzotriazole or N-hydroxysuccinimide; symmetric acidanhydrides and mixed acid anhydrides thereof with alkylcarbonic acid orp-toluenesulfonic acid.

When a compound (II) is used as a free acid, it is preferable to carryout the above reaction in the presence of a condensing agent undercooling with ice or under reflux by heating. Examples of the condensingagent include dicyclohexylcarbodiimide, 1,1'-carbonyldiimidazole, ethylchloroformate, diethyl azodicarboxylate and dipyridyl disulfide.

The reaction may be carried out in water or an inert organic solvent byusing a compound (II) or a reactive derivative thereof and a compound(III) in molar amounts which are nearly equal to each other or one ofwhich is slightly larger than the other. Examples of the inert organicsolvent include methanol, ethanol, pyridine, tetrahydrofuran, dioxane,ether, benzene, toluene, xylene, methylene chloride, dichloroethane,chloroform, dimethylformamide, ethyl acetate and acetonitrile.

Depending upon the kind of the reactive derivative, it is advantageousfrom the standpoint of the smoothness of the reaction to use a base suchas diisopropylethylamine, triethylamine, pyridine, picoline, lutidine,N,N-dimethylaniline, 4-dimethylaminopyridine, potassium carbonate orsodium hydroxide.

The reaction temperature is not particularly limited but variesdepending upon the kind of the reactive derivative. Generally, thereaction is carried out at a temperature of from -20° C. to refluxtemperature to obtain the objective compound.

The compound represented by the general formula (II) to be used as astarting material in the present invention can be prepared by, forexample, the following process: ##STR17## (In the above formulas, R¹ isas defined above and Ph is a phenyl group)

STEP 1

In this step, a compound represented by the general formula (V) isreacted with a compound represented by the general formula (IV) in thepresence of a copper catalyst such as copper powder or copper oxideunder heating to carry out an Ullmann reaction. Thus, a compound (VI) isobtained. This reaction may be carried out in the absence of any solventor in the presence of an inert organic solvent such as nitrobenzene,dimethylformamide or pyridine, or water.

Alternatively, a compound represented by the general formula (VI) may beprepared by reacting a compound represented by the general formula (V)with a salt of a compound represented by the general formula (IV) with ametal such as lithium, sodium or potassium and subjecting the obtainedintermediate to a replacement reaction or the like.

This reaction may be carried out in the absence of any solvent or in thepresence of an inert organic solvent such as dimethylformamide,dimethylacetamide, dimethyl sulfoxide, dioxane, ether ortetrahydrofuran.

STEP 2

A compound represented by the general formula (VI) is reacted with acompound represented by the general formula (VI') in the presence ofpotassium t-butoxide, caustic potash, caustic soda, sodium methoxide,sodium ethoxide or sodium hydride in a suitable solvent at a temperatureof -78° C. to a room temperature according to an ordinary process toobtain a compound (II). Examples of the solvent include ether,tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide anddimethyl sulfoxide.

Further, a compound represented by the general formula (VI) may be alsoprepared by the following process: ##STR18## (in the above formulas, R¹is as defined above)

Namely, a compound represented by the general formula (VII) is reactedwith metallic magnesium under heating in a solvent such as ether ortetrahydrofuran, if necessary, in the presence of an iodine as acatalyst to obtain a Grignard reagent (VIII). This Grignard reagent isreacted with a halide represented by the formula (IX) in the presence ofa metal complex catalyst at a room or elevated temperature or underreflux by heating according to an ordinary process to obtain a compoundrepresented by the general formula (X). Examples of the catalyst includebis(1,3-diphenylphosphinopropane)nickel (II) chloride andtetrakis(triphenylphosphine)palladium. The compound represented by thegeneral formula (X) is deacetalized with an acid to obtain a compound(VI).

The compound (III) to be used as the other starting material can beprepared by, for example, the following processes: ##STR19## (in theabove formulas, R², R³, n, A and J are each as defined above)

STEP 1

In this step, a compound represented by the formula (XI) is reacted witha compound represented by the formula (XII) according to an ordinaryprocess to obtain a compound (XIII).

More specifically, the above reaction is carried out in a suitablesolvent in the presence of a base such as potassium carbonate, sodiumcarbonate, triethylamine or diisopropylethylamine under heating toobtain a compound (XIII). Examples of the solvent include benzene,toluene, xylene, dimethylformamide, acetonitrile, dimethyl sulfoxide,dioxane and tetrahydrofuran.

STEP 2

When Y is a leaving group such as a halogen atom or a methanesulfonyloxygroup, the compound (XIII) is reacted with an alkali metal salt ofphthalimide (XIV) such as potassium or sodium salt thereof in thepresence of a base such as potassium carbonate or sodium carbonate toobtain a compound (XV). On the other hand, when Y is a protectedhydroxyl group such as a trityloxy or t-butyldimethylsiloxy group, thecompound (XIII) is freed of the protective group according to anordinary method and subjected to the Mitsunobu reaction withphthalimide, triphenylphosphine or diethyl azodicarboxylate to obtain acompound (XV). In this case, it is preferable to use an inert solventsuch as dimethyl sulfoxide, dimethylformamide, dimethylacetamide,acetonitrile or tetrahydrofuran

STEP 3

A compound represented by formula (XV) is reacted with, for example,hydrazine monohydrate in an organic solvent such as methanol or ethanolunder reflux to obtain a compound (III') (corresponding to a compound offormula (III) wherein R² is a hydrogen atom).

STEP 4

A compound represented by formula (III') (corresponding to a compound offormula (III) wherein R² is a hydrogen atom) is reacted with an aldehydeor ketone in the presence of a catalyst such as palladium/carbon,platinum oxide or Raney nickel in a hydrogen atmosphere to carry outreductive amination. Thus, a compound represented by formula (III) isobtained.

The aldehyde and ketone to be used in this step include acetone,cyclobutanone, cyclopentanone and benzaldehyde. A solvent may be used inthis step and examples thereof include methanol, ethanol, benzene,toluene, xylene, dimethylformamide, tetrahydrofuran, dioxane and ethylacetate

Alternatively, a compound represented by formula (III) can be preparedby converting a compound represented by formula (III') into an amide orcarbamate thereof, for example, N-formyl, N-acetyl, N-methoxycarbonyl orN-ethoxycarbonyl derivative according to an ordinary process andreducing the obtained amide or carbamate in the presence of a metalhydride complex such as lithium aluminum hydride or boran.

This reduction may be carried out in a solvent at a room or elevatedtemperature or under reflux by heating and examples of the solventinclude ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane anddiethylene glycol dimethyl ether.

Further, a compound (XV) can be also prepared by the following process:##STR20##

Namely, a compound represented by formula (XI) is reacted with acompound (XVI) in the presence of a base such as potassium carbonate,sodium carbonate, caustic soda, triethylamine or diisopropylethylamineat a room or elevated temperature or under reflux by heating to obtain acompound (XV). A suitable solvent may be used in this step and examplesthereof include dimethyl sulfoxide, dimethylformamide, dimethylacetamideand acetonitrile. ##STR21##

STEP 1

A compound represented by formula (XI) is reacted with a compoundrepresented by formula (XVII) in the absence of any solvent or in thepresence of a solvent such as dichloromethane, chloroform, acetonitrile,dimethylformamide, dimethyl sulfoxide, ether, tetrahydrofuran, methanolor ethanol under heating or reflux to obtain a compound (XVIII).

STEP 2

A compound represented by formula (XVIII) is hydrogenated in thepresence of a catalyst such as palladium/carbon, platinum oxide or Raneynickel to obtain a compound represented by the formula (III').

The hydrogenation is carried out in a solvent such as methanol, ethanol,dimethylformamide of ethyl acetate under an ordinary or elevatedpressure at an ordinary or elevated temperature. ##STR22##

The invention further provides the pharmacological use of the compoundsof the invention. A pharmacological composition of the inventioncomprises a pharmacologically effective amount of the butenoic orpropenoic acid derivative as defined by the formula II and apharmacologically acceptable carrier. Further here is provides a methodfor treating, preventing, remitting or ameliorating ischemic heartdiseases by administering the butenoic or protenoic acid derivativehaving the formula II in a pharmacologically effective amount to a humanbeing. The compound of the invention provides, in particular, anexcellent coronary vasodilating and heart rate lowering effect.

Accordingly, the compound of the present invention is effective for thetreatment, prevention, remission or amelioration of ischemic heartdiseases such as coronary sclerosis, various angina pectoris or cardiacinfarction.

When the compound of the present invention is to be used as a drug, itmay be administered either orally or parenterally. The dose variesdepending upon the degree of symptoms; the age, sex, weight andsensitivity of a patient; the method, timing and interval ofadministration; the properties, preparation method and kind of a drug orthe kind of an active ingredient and therefore is not particularlylimited. Generally, the dose is about 1 to 1000 mg, preferably about 5to 500 mg, still preferably about 50 to 200 mg. It is generallyadministered at once or in 2 to 4 portions.

A solid drug containing the compound of the present invention for oraladministration may be prepared by mixing a compound of the presentinvention with a filler and, if necessary, binder, disintegrator,lubricant, coloring agent or corrigent and shaping the obtained mixtureinto tablet, coated tablet, granule, powder or capsule.

Examples of the filler include lactose, corn starch, sucrose, glucose,sorbitol, crystalline cellulose and silicon dioxide. Examples of thebinder include polyvinyl alcohol, polyvinyl ether, ethylcellulose,methylcellulose, acacia, tragacanth, gelatin, shellac,hydroxypropylcellulose, hydroxypropylmethylcellulose, calcium citrate,dextrin and pectin. Examples of the lubricant include magnesiumstearate, talc, polyethylene glycol, silica and hardened vegetable oils.The coloring agent may be any one permitted to be added to a drug. Thecorrigent includes cacao powder, mentha herb, aromatic powder, menthaoil, borneol and powdered cinnamon bark. Of course, the tablet orgranule may be coated with sugar, gelatin or the like.

An injection containing the compound of the present invention can beprepared by mixing a compound of the present invention as a principalagent with pH adjustor, buffer, suspending agent, solubilizing agent,stabilizer, tonicity agent or preservative and treating the obtainedmixture by an ordinary process to obtain an intravenous, subcutaneous orintramuscular injection. If necessary, the injection may be freeze-driedby an ordinary method.

Examples of the suspending agent include methylcellulose, Polysorbate80, hydroxyethylcellulose, acacia, tragacanth powder, sodiumcarboxymethylcellulose and polyoxyethylene sorbitan monolaurate.

Examples of the solubilizing agent include polyoxyethylene hardenedcastor oil, Polysorbate 80, nicotinamide, polyoxymethylene sorbitanmonolaurate, macrogol and ethyl ester of castor oil fatty acid

Examples of the stabilizer include sodium sulfite, sodium metasulfiteand ether, while those of the preservative include methylp-hydroxybenzoate, ethyl p-hydroxybenzoate, sorbic acid, phenol, cresoland chlorocresol.

A compound represented by the formula (XIX) is reacted with a compound(XX) in the presence of a base such as potassium carbonate, sodiumcarbonate, caustic soda, triethylamine or diisopropylethylamine at aroom or enhanced temperature or under reflux to obtain a compound (III).

A suitable solvent may be used in this process and examples of thesolvent include dimethyl sulfoxide, dimethylformamide, dimethylacetamideand acetonitrile.

EMBODIMENT (II)

In the embodiment (II), it is preferable that G is the phenyl having R15and R16, R15 and R16 each are hydrogen, a halogen, cyano, a loweralkoxy, --NR7R8, R7 and R8 each being hydrogen or a lower alkyl, analkylthio or an alkanoylamino, or R15 and R16 may form a cyclic ringtogether with oxygen and the two adjacent carbon atoms, R11 and R12 eachare hydrogen, m is zero or 1, X is oxygen, R2 is hydrogen or may form acyclic ring together with R12, A is an alkylene having 1 to 3 carbonatoms, R3 is a lower alkyl, n is an integer of 1 to 3, J is the phenylhaving R4, R5 and R6, R4, R5 and R6 each are hydrogen or a lower alkyl.

It is also preferable that J is m-dimethoxy-phenyl orm,p-dimethoxy-phenyl.

When R2 or R3 forms a heterocyclic ring with A, the following two arepreferable: ##STR23##

Also in the embodiments (II), preferable groups for the lower alkyl, thelower alkoxy and the cycloalkyl are defined in the same way as shown inthe emobodiments (I).

It is more preferable that R15 and R16 are a halogen such as fluorine,cyano, a lower alkoxy such as methoxy and ethoxy, a mono- or di-loweralkylamino such as dimethylamino, an alkylthio such as methylthio, analkanoylamino such as CH3CONH-- and methylenedioxy.

It is preferable that R11 and R12 are hydrogen at the same time.

Preferable groups of --NR2--A--NR3-- are defined in the same way asshown in the embodiment (I).

Most preferable compounds are:

(E)-N-(3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)-amino)propyl)-4-(4-fluorophenyl)-3-buteneamide,

(E)-N-(3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)-3-(4-fluorophenyl)propeneamide,

(E)-N-(3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)-3-(4-cyanophenyl)propeneamide,

(E)-N-(3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)-4-(3,4-(methylenedioxy)phenyl)-3-buteneamide,

(E)-N-(3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)-4-(4-cyanophenyl)-3-buteneamide,

(E)-N-(3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)-4-(3,4-dimethoxyphenyl)-3-buteneamide,

(E)-N-(3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)-4-(4-(dimethylamino)phenyl)-3-buteneamide,

(E)-N-(3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)-4-(4-(methylthio)phenyl)-3-buteneamide,

(E)-N-(3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)-4-(4-chlorophenyl)-3-buteneamide,

(E)-N-(3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)-4-(4-methoxyphenyl)-3-buteneamide,

(E)-N-(3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)-4-(4-(acetylamino)phenyl)-3-buteneamide,

(E)-N-(3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)-3-(4-fluorobenzylidene)-2-pyrrolidinoneand

(E)-N-(3-((N'-(2(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)-3-(4-cyanobenzylidene)-2-pyrrolidinone.

The above shown compounds are defined by the following formulae,respectively. ##STR24##

Typical preparation methods for the compounds according to the presentinvention are explained below. ##STR25## where R¹, R², R³, R⁴, X, m, n,G, A and J in each of the formulae have the same meanings as describedabove.

That is, the aimed compound (I) can be obtained by amidizing acarboxylic acid or thiocarboxylic acid represented by the generalformula (II) or the reactive derivative thereof with an amino compoundrepresented by the general formula (III).

As the reactive derivative of the compound (II), there can be mentionedactive esters with acid halide such as acid chloride or acid bromide,acid azide, N-hydroxybenzotriazole or n-hydroxysuccinic imide, mixedacid anhydride with symmetric acid anhydride, alkyl carbonic acid,p-toluene sulfonic acid or phosphoric acid ester, etc.

When free carboxylic acid is used as the compound (II), it is preferredto react under the presence of a condensating agent such as dicyclohexylcarbodiimide, 1,1'-carbonyl diimidazole, chloroformate, diethylazodicarboxylate, dipyridyldisulfide, etc. under ice cooling orheat-refluxing.

The reaction was carried out by using a compound (II) or the reactivederivative thereof and a compound (III) substantially in an equi-molarratio or at a slight excess molar ratio of one of them, in a solventsuch as water or an organic solvent inert to the reaction, for example,methanol, ethanol, pyridine, tetrahydrofuran, dioxane, ether, benzene,toluene, xylene, methylene chloride, dichloroethane, chloroform,dimethylformamide, methylene chloride, ethyl acetate and acetonitrile.

Depending on the kind of the reactive derivative, it may be some timeadvantageous to add a base such as diisopropyl ethylamine,triethylamine, pyridine, picoline, lutidine, N,N-dimethylaniline,4-dimethylaminopyridine, potassium carbonate or sodium hydroxide uponreaction in view of smooth proceeding of the reaction.

The reaction temperature varies depending on the kind of the reactivederivative and has no particular restriction, and the aimed compound canusually be obtained by reaction at a temperature from -20° C. toheat-refluxing temperature.

Further, the compound (I) can also be prepared by the following method:##STR26## where R¹, R², R³, R⁴, X, m, n, G, A and J in each of theformulae have the same meanings as described above.

FIRST STEP

In this the step, the compound (V) is formed by amidizing a carboxylicacid or thiocarboxylic acid represented by the general formula (II) orthe reactive derivative thereof by the reaction with an amino compoundrepresented by the general formula (IV).

As the reactive derivative of the compound (II), there can be mentionedactive esters with acid halide such as acid chloride or acid bromide,acid azide, N-hydroxybenzotriazole or n-hydroxysuccin imide, mixed acidanhydride with symmetric acid anhydride, alkyl carbonic acid, p-toluenesulfonic acid or phosphoric acid ester, etc.

When free carboxylic acid is used as the compound (II), it is preferredto react under the presence of a condensating agent such as dicyclohexylcorbodiimide, 1,1'-carbonyl diimidazole, chloroformate, diethylazodicarboxylate, dipyridyldisulfide, etc. under ice cooling or heatrefluxing.

The reaction was carried out by using a compound (II) or the reactivederivative thereof and a compound (III) substantially in an equi-molarratio or at a slight excess molar ratio of one of them, in a solventsuch as water or an organic solvent inert to the reaction, for example,methanol, ethanol, pyridine, tetrahydrofuran, dioxane, ether, benzene,toluene, xylene, methylene chloride, dichloroethane, chloroform,dimethylformamide, methylene chloride, ethyl acetate and acetonitrile.

Depending on the kind of the reactive derivative, it may be some timeadvantageous to add a base such as diisopropyl ethylamine,triethylamine, pyridine, picoline, lutidine, N,N-dimethylaniline,4-dimethylaminopyridine, potassium carbonate or sodium hydroxide uponreaction, in view of smooth proceeding of the reaction.

The reaction temperature varies depending on the kind of the reactivederivative and has no particular restriction, and the aimed compound canusually be obtained by reaction at a temperature from -20° C. toheat-reflux temperature.

SECOND STEP

In this step, the aimed compound (I) is formed by reacting a compoundrepresented by the general formula (V) with a compound represented bythe general formula (VI) by a customary method.

That is, the compound (I) is formed by reacting a compound representedby the formula (V) with a compound (VI) at a temperature from a roomtemperature to a refluxing temperature under the presence of a base suchas potassium carbonate, sodium carbonate, triethylamine and diisopropylethylamine.

In this case, solvent such as benzene, toluene, xylene,dimethylsulfoxide, dimethylformamide, dimethylacetoamide andacetonitrile can be used.

The compound (V) can also be formed by the following method ##STR27##where R¹, R², R³, R⁴, X, m, n, G, A and J in each of the formulae havethe same meanings as described above providing that R³ is not H.

That is, the compound (V) can be formed by reacting a compoundrepresented by the general formula (VIII) and a compound represented bythe general formula (VII) by a customary method at a temperature from anice cooled temperature to a heat refluxing temperature by using asolvent, for example, ether, tetrahydrofuran, dioxane,dimethylformamide, dimethylacetoamide and dimethylsulfoxide, under thepresence of potassium tert-butoxide, sodium methoxide, sodium ethoxide,sodium amide, sodium hydride and potassium hydride.

Among the compounds represented by the general formula (II) used as thestarting material in the present invention, those compounds in wich R¹=R² =H, m=1, X=0 can be formed, for example, by the following method.##STR28## where G has the same meanings as described above and Phrepresents phenyl group in each of the formulae.

FIRST STEP

The compound (II') can be formed by reacting a compound represented bythe general formula (IX) and a compound represented by the generalformula (X) by a customary method at a temperature from -78° C. to aroom temperature by using a solvent, for example, ether,tetrahydrofuran, dioxane, dimethylformamide, dimethylacetoamide ordimethylsulfoxide and under the presence of potassium t-butoxide,potassium hydroxide, sodium hydroxide, sodium methoxide, sodium ethoxideor sodium hydride.

Further, the compound (III) as the starting material can be prepared,for example, by the following preparation method. ##STR29## where R³,R⁴, n, A and J in each of the formulae have the same meanings asdescribed above.

FIRST STEP

In this step, the compound (XIII) is formed by reacting a compoundrepresented by the formula (XI) and a compound represented by theformula (XII) by a customary method.

Specifically, the compound (XIII) is formed by reacting both of thecompounds at a temperature from a room temperature to a heat refluxingtemperature by using a solvent, for example, benzene, toluene, xylene,dimethylformamide, acetonitrile, dimethylsulfoxide, dioxane andtetrahydrofuran and under the presence of a base, for example, potassiumcarbonate, sodium carbonate, triethylamine and diisopropylethylamine.

SECOND STEP

A compound (III'), where R³ =H in the formula (III), can be formed byreacting a compound represented by the formula (XIII), for example, witha hydrazine monohydrate under heat reflux in the presence of an organicsolvent such as methanol or ethanol.

THIRD STEP

A compound represented by the formula (III) can be formed by conductingamidizing reduction between a compound represented by the formula(III'), in which R³ =H in the formula (III), and an aldehyde or ketoneby using a catalyst such as palladium-carbon, platinum oxide, Raneynickel, etc. in a hydrogen atmosphere.

In this case, acetone, cyclobutanone, cyclopentanone or benzaldehyde canbe used as the aldehyde or ketone. As the reaction solvent, there can beused methanol, ethanol, benzene, toluene, xylene, dimethylformamide,tetrahydrofuran, dioxane and ethyl acetate.

As an alternative method, a compound represented by the formula (III)can be formed by converting a compound represented by the formula (III')into an acidamide or carbamate, for example, N-formyl, N-acetyl,N-methoxycarbonyl or N-ethoxycarbonyl by a customary method, which isthen reduced with a metal hydrogen complex compound, for example,aluminum lithium hydride or borane.

The reductive reaction is conducted at a temperature from a roomtemperature to a heat refluxing temperature by using a solvent such asether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethylene glycoldimethyl ether, etc. ##STR30## where R⁴, n, A and J in each of theformulae have the same meanings as described above and Hal represents ahalogen atom.

FIRST STEP

The compound (XV) can be prepared by reacting a compound represented bythe formula (XI) and a compound represented by a formula (XIV) at atemperature from a room temperature to a heat refluxing temperaturewithout using solvent or under the presence of a solvent such asdichloromethane, chloroform, acetonitrile, dimethylformaide,dimethylsulfoxide, ether, tetrahydrofuran, methanol, ethanol, etc.

SECOND STEP

The compound represented by the formula (III') can be prepared bysubjecting a compound represented by the formula (XV) to a hydrogenatingreaction by using a catalyst such as palladium-carbon, platinum oxide orRaney nickel.

In this case, the reaction is conducted under the pressure from a normalpressure to an elevated pressure and at a temperature from a normaltemperature to an elevated temperature while using a solvent, forexample, methanol, ethanol, dimethylformamide and ethyl acetate.##STR31## where R³, R⁴, n, A, J in each of the formulae have the samemeanings as described above.

The compound (III) can be prepared by reacting a compound represented bythe formula (XVI) with a compound (XVII) at a temperature from a roomtemperature to a heat refluxing temperature under the presence of a basesuch as potassium carbonate, sodium carbonate, sodium hydroxide,triethylamine and diisopropylethylamine.

As the reaction solvent used in this case, there can be used, forexample, those solvents such as dimethylsulfoxide, dimetylformamide,dimethylacetoamide or acetonitrile.

EMBODIMENT (III)

This is defined with the above shown formula (III).

It is preferable that W is azomethyne or sulfur (--S--) and R2 ishydrogen.

The heterocyclic ring for R31 has the same preferable groups as shownfor R1. In addition, there is included a heteroaryl having a nitrogen(s)such as pyridazinyl, pyrazinyl, 1,2-dihydro-2-oxopyridyl, anenantiomorphic isomer thereof, 2,3-dihydro-3-oxopyridazinyl and anenantiomorphic isomer thereof. A heterocyclic ring having nitrogen andsulfur includes thiazolyl, isothiazolyl.

A preferable ring formed from R3, N and --(CH2)n-- includes: ##STR32##

A preferable ring formed from R3, A and N includes: ##STR33##

The lower alkyl, the lower alkoxy and the cycloalkyl are defined fortheir preferble groups in the same way as shown in the embodiment (I).

The ring formed from R2, R3, N, A and N includes: ##STR34##

Preferable groups for R4, R5 and R6 are defined in the same way as shownin the embodiment (I).

Most preferable compounds are:

(E)-N-(3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)-4-(4-(2-pyrazinyl)phenyl)-3-buteneamide,

(E)-N-(3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)-4-(4-(1,3-thiazol-4-yl)phenyl)-3-buteneamide,

(E)-N-(3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)-4-(4-(2-methyl-1,3-thiazol-4-yl)phenyl)-3-buteneamide,

(E)-N-(3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)-4-(3-(1H-imidazol-1-yl)thiophene-5-yl)-3-buteneamide,

(E)-N-(3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)-4-(2-(1H-imidazol-1-yl)thiophene-5-yl)-3-buteneamide,

(E)-N-(N'(2-(3,4-dimethoxyphenyl)ethyl)-3-pyrrolidinyl)-4-(4-(1H-imidazol-1-yl)phenyl)-3-buteneamide,

(E)-N-(2-(N'-(2-(3,4-dimethoxypehnyl)ethyl)-2-pyrrolidinylethyl)-4-(4-(1H-imidazol-1-yl)phenyl)-3-buteneamide,

(E)-N-(2-(N'-(2-(3,4-dimethoxyphenyl)ethyl-2-pyperidinoethyl)-4-(4-(1H-imidazol-1-yl)phenyl-3-buteneamide,

(E)-N-(3-((N'-(2-(3,5-dimethoxyphenyl)ethyl)-N'-methyl)amino)-2-hydroxypropyl)-4-(4-(1H-imidazol-1-yl)phenyl)-3-buteneamideand

(E)-N-(1-(2-(3,4-dimethoxyphenyl)ethyl)-4-piperidinyl)-4-(4-(1H-imidazol-1-yl)phenyl)-3-buteneamide.

The above listed compounds have the following formulae, respectively.##STR35##

Preparation methods for the embodiments III are described below inreference to examples in which W is vinylene. The methods apply to theother groups than vinylene for W. ##STR36## where R¹, R², R³, n, and Jin each of the formulae have the same meanings as described above.

That is, the aimed compound (I) can be obtained by amidizing acarboxylic acid acid represented by the general formula (II) or thereactive derivative thereof with an amino compound represented by thegeneral formula (III).

As the reactive derivative of the compound (II), there can be mentionedactive esters with acid halide such as acid chloride or acid bromide,acid azide, N-hydroxybenzotriazole or n-hydroxysuccinic imide, mixedacid anhydride with symmetric acid anhydride, alkyl carbonic acid,p-toluene sulfonic acid or phosphoric acid ester, etc.

When free carboxylic acid is used as the compound (II), it is preferredto react under the presence of a condensating agent such as dicyclohexylcarbodiimide, 1,1'-carbonyl diimidazole, chloroformate, diethylazodicarboxylate, dipyridyldisulfide, etc. under ice cooling orheat-refluxing.

The reaction was carried out by using a compound (II) or the reactivederivative thereof and a compound (III) substantially in an equi-molarratio or at a slight excess molar ratio of one of them, in a solventsuch as water or an organic solvent inert to the reaction, for example,methanol, ethanol, pyridine, tetrahydrofuran, dioxane, ether, benzene,toluene, xylene, methylene chloride, dichloroethane, chloroform,dimethylformamide, methylene chloride, ethyl acetate and acetonitrile.

Depending on the kind of the reactive derivative, it may be some timeadvantageous to add a base such as diisopropyl ethylamine, triethylaine,pyridine, picoline, lutidine, N,N-dimethylaniline,4-dimethylaminopyridine, potassium carbonate or sodium hydroxide uponreaction in view of smooth proceeding of the reaction.

The reaction temperature varies depending on the kind of the reactivederivative and has no particular restriction, and the aimed compound canusually be obtained by reaction at a temperature from -20° C. toheat-refluxing temperature.

The compound represented by the general formula (II) used as thestarting material in the present invention can be prepared, for example,by the following method. ##STR37## where R¹ in each of the formulae hasthe same meanings as described above and Ph represents phenyl group.

FIRST STEP

In this the step, the compound (VI) is formed by subjecting a compoundrepresented by the general formula (V) and a compound represented by thegeneral formula (IV) to Ullmann type reaction under heating using acopper catalyst such as copper powder or copper oxide.

In this case, the reaction can be carried out without solvent or byusing those inert organic solvents not relevant to the reaction, forexample nitrobenzene, dimethylformamide, pyridine or water.

As another method of forming the compound represented by the generalformula (VI), there can be mentioned a method of reacting a compoundrepresented by the general formula (V) with a compound represented bythe general formula (IV) after being converted into a metal salt such asof lithium, sodium or potassium and then preparing the compound (VI) bysubstituting reaction, etc.

The reaction can be carried out without using solvent or by using thoseinert organic solvents not relevant to the reaction, for example,dimethylformamide, dimethylacetoamide, dimethylsulfoxide, dioxane, etherand tetrahydrofuran.

SECOND STEP

The compound (II) can be formed by reacting a compound represented bythe general formula (VI) and a compound represented by the generalformula (VI') by a customary method at a temperature from -78° C. to aroom temperature by using a solvent, for example, ether,tetrahydrofuran, dioxane, dimethylformamide, dimethylacetoamide anddimethylsulfoxide, under the presence of potassium tert-butoxide, sodiummethoxide, sodium ethoxide, sodium amide, sodium hydride and potassiumhydride.

Another method of forming the compound represented by the generalformula (VI) is shown below: ##STR38## where R¹ has the same meanings asdescribed above in each of the formulae.

That is, a compound represented by the general formula (VII) is heatedtogether with metal magnesium under the presence of a solvent such asether or tetrahydrofuran and with addition of iodine as a catalyst ifrequired, to prepare a Grignard reagent (VIII). Then, it is reacted witha halide represented by the formula (IX) with addition of a metalcomplex as a catalyst, for example, bis(1,3-diphenylphosphinopropane)nickel (II) chloride or tetrakistriphenylphisphine palladium by acustomary method at a temperature from a room temperature to a heatrefluxing temperature to prepare a compound represented by the generalformula (X). Then, the compound is deacetalized with an acid to obtain acompound represented by the general formula (VI).

Further, the compound (III) as the starting material can be prepared,for example, by the following preparation method. ##STR39## where R²,R³, n, A and J in each of the formulae have the same meanings asdescribed above.

FIRST STEP

In this step, the compound (XIII) is formed by reacting a compoundrepresented by the formula (XI) and a compound represented by theformula (XII) by a customary method.

Specifically, the compound (XIII) is formed by reacting both of thecompounds at a temperature from a room temperature to a heat refluxingtemperature by using a solvent, for example, benzene, toluene, xylene,dimethylformamide, acetonitrile, dimethylsulfoxide, dioxane andtetrahydrofuran and under the presence of a base, for example, potassiumcarbonate, sodium carbonate, triethylamine and diisopropylethylamine.

SECOND STEP

In a case where Y represents a stripping group, for example, a halogenatom or methane sulfonyloxy, a compound represented by the formula(XIII) is reacted with an alkali metal salt of phthalimide representedby the formula (XIV) such as potassium phthalimide or sodium phthalimideunder the presence of a base such as potassium carbonate or sodiumcarbonate, to form a compound represented by the formula (XV). When Y isa protected hydroxy, for example trityloxy or tert-butyldimethylsiloxy,the protecting group is removed by a conventional method and thenMitsunobu reaction using phthalimide, trimethylphosphine anddiethylazodicarboxylate is conducted to prepare a compound of theformula (XV). In this case, an inert solvent not relevant to thereaction, preferably, dimethylsulfoxide, dimethylformamide,dimethylacetoamide, acetonitrile, tetrahydrofuran, etc. are used as thesolvent.

THIRD STEP

A compound (III'), where R³ =H in the formula (III), can be formed byreacting a compound represented by the formula (XV), for example, with ahydrazine monohydrate under heat reflux in the presence of a organicsolvent such as methanol or ethanol.

FOURTH STEP

A compound represented by the formula (III) can be formed by conductingamidizing reduction between a compound represented by the formula(III'), in which R³ =H in the formula (III), and an aldehyde or ketoneby using a catalyst such as palladium-carbon, platinum oxide, Raneynickel, etc. in a hydrogen atmosphere.

In this case, acetone, cyclobutanone, cyclopentanone or benzaldehyde canbe used as the aldehyde or ketone. As the reaction solvent, there can beused methanol, ethanol, benzene, toluene, xylene, dimethylformamide,tetrahydrofuran, dioxane and ethyl acetate.

As an alternative method, a compound represented by the formula (III)can be formed by converting a compound represented by the formula (III')into an acidamide or carbamate, for example, N-formyl, N-acetyl,N-methoxycarbonyl or N-ethoxycarbonyl by a customary method, which isthen reduced with a metal hydrogen complex compound, for example,aluminum lithium hydride or borane.

The reductive reaction is conducted at a temperature from a roomtemperature to a heat refluxing temperature by using a solvent such asether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethylene glycoldimethyl ether, etc.

The compound (XV) can also be obtained by the following method.##STR40##

That is, a compound of the formula (XV) is formed by reacting a compoundrepresented by the formula (XI) with a compound represented by theformula (XVI) under the presence of a base, for example, potassiumcarbonate, sodium carbonate, sodium hydroxide, triethylamine anddiisopropyisoethylamine at a temperature from a room temperature to arefluxing temperature.

In this case, those solvents, for example, dimethylsulfoxide,dimethylformamide, dimethylacetoamide and acetonitrile can be used asthe solvent. ##STR41##

FIRST STEP

The compound (XVIII) can be formed by reacting a compound represented bythe formula (XI) and a compound represented by the formula (XVII) at atemperature from a room temperature to a heat refluxing temperaturewithout using solvent or under the presence of a solvent such asdichloromethane, chloroform, acetonitrile, dimethylformaide,dimethylsulfoxide, ether, tetrahydrofuran, methanol, ethanol, etc.

SECOND STEP

The compound represented by the formula (III') can be formed bysubjecting a compound represented by the formula (XVIII) to ahydrogenating reaction by using a catalyst such as palladium-carbon,platinum oxide or Raney nickel.

In this case, the reaction is conducted under the pressure from a normalpressure to an elevated pressure and at a temperature from a normaltemperature to an elevated temperature while using a solvent, forexample, methanol, ethanol, dimethylformamide and ethyl acetate.##STR42##

The compound (III) can be formed by reacting a compound represented bythe formula (XIX) with a compound of the formula (XX) at a temperaturefrom a room temperature to a heat refluxing temperature under thepresence of a base such as potassium carbonate, sodium carbonate, sodiumhydroxide, triethylamine and diisopropylethylamine.

As the reaction solvent used in this case, there can be used, forexample, those solvents such as dimethylsulfoxide, dimetylformamide,dimethylacetoamide or acetonitrile.

PHARMACOLOGICAL TEST

Pharmacological tests were conducted for the compounds of the inventionincluding the embodiments I, II and III, in view of (1) the effect uponcardiac muscle extirpated from guinea pig, (2) the heart rate loweringand coronary bloodflow increasing effects upon anesthetizedthoracotomized dog and (3) the toxicity.

The test compounds, A to M of I, A to J of II and A to E of III arelisted below.

COMPOUNDS A TO M OF I

Compound A (compound of Example 1)

(E)-N-[3-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(1H-imidazol-1-yl)phenyl)-3-butenamide

Compound B (compound of Example 2)

(E)-N-[3-((N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(1H-imidazol-1-yl)phenyl)-3-butenamide

Compound C (compound of Example 3)

(E)-N-[3-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-(4-(1H-imidazol-1-yl)phenyl)-3-butenamide

Compound D (compound of Example 19)

(E)-N-[3-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(3-pyridyl)phenyl)-3-butenamide

Compound E (compound of Example 23)

(E)-N-[3-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(1H-pyrrol-1-yl)phenyl)-3-butenamide

Compound F (compound of Example 26)

(E)-N-[3-((N'-(2-(3,4-Dimethoxyphenyl)ethyl-N'-methyl)amino)propyl]-4-(4-(1H-benzimidazol-1-yl)phenyl)-3-butenamide

Compound G (compound of Example 9)

(E)-N-[3-((N'-(2-Phenylethyl)-N'-methyl)amino)propyl]-4-(4-(1H-imidazol-1-yl)phenyl)-3-butenamide

Compound H (compound of Example 10)

(E)-N-[3((N'-(2-(3,4,5-Trimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(1H-imidazol-1-yl)phenyl)-3-butenamide

Compound I (compound of Example 29)

(E)-N-[3-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl-4-(4-(4(1H)-pyridon-1-yl)phenyl)-3-butenamide

Compound J (compound of Example 7)

(E)-N-[3-((N'-(2-(3-Methoxyphenyl)ethyl)-N'-methyl)amino1H)propyl]-4-(4-(1H-imidazol-1-yl)phenyl)-3-butenamide

Compound K (compound of Example 13)

(E)-N-[3-((N'-(2-(3,4-Methylenedioxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(1H-imidazol-1-yl)phenyl)-3-butenamide

Compound L (compound of Example 18)

(E)-N-[3-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(4-methyl-1H-imidazol-1-yl)phenyl)-3-butenamide

Compound M (compound of Example 25)

(E)-N-[3-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(1H-1,2,4-triazol-1-yl)phenyl)-3-butenamide

COMPOUNDS A TO J OF II

A:

(E)-N-(3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)-4-(4-fluorophenyl)-3-buteneamidedihydrochloride,

B:

(E)-N-(3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)-4-(3,4-methylenedioxy)phenyl)-3-buteneamidedihydrochloride,

C:

(E)-N-(3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)-3-(4-fluorophenyl)propeneamide,

D:

(E)-N-(3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)-3-(4-cyanophenyl)propeneamide,

E:

(E)-N-(3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)-3-(4-fluorobenzylidene)-2-pyrrolidinone,

F:

(E)-N-(3-((N'-(2-(4-methoxyphenyl)ethyl)-N'-allyl)amino)propyl)-3-(4-fluorophenyl)propeneamide,

G:

(E)-N-(3-((N'-(3-(3,4-dimethoxyphenyl)pyrrolidine-1-yl)propyl)-3-(4-fluorophenyl)-propeneamide,

H:

(E)-N-(3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)-4-(4-methoxyphenyl)-3-buteneamide,

I:

(E)-N-(3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl-4-(3,4,5-trimethoxyphenyl)-3-buteneamide,

J:

(E)-N-(3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)-N-cyclopentyl-4-(4-cyanophenyl)-3-buteneamide,

COMPOUNDS A TO E OF III

A:

(E)-N-(3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)-4-(4-(1,3-thiazol-4-yl)phenyl)-3-buteneamide,

B:

(E)-N-(N'-(2-(3,4-dimethoxyphenyl)ethyl)-3-pyrrolidino)-4-(4-(1H-imidazol-1-yl)phenyl)-3-buteneamide,

C:

(E)-N-(2-(N'-(2-(3,4-dimethoxypehnyl)ethyl)-2-pyrrolidino)ethyl)-4-(4-(1H-imidazol-1-yl)phenyl)-3-buteneamide,

D:

(E)-N-(3-(N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)-4-(4-(1H-imidazol-1-yl)thiophene-2-yl)-3-buteneamide,

E:

(E)-N-(3-((N'-(3-(3,4-dimethoxyphenyl)-2-propyl)-N'-methyl)amino)propyl)-4-(4-(1H-imidazol-1-yl)phenyl)-3-buteneamide.

Now, Pharmacological Experiment Examples will be described to illustratethe effect of the compound of the present invention in more detail.

PHARMACOLOGICAL EXPERIMENT EXAMPLE Experimental Example 1 Effect UponCardiac Muscle Extirpated From Guinea Pig

The effect of the compound (test compound) of the present invention uponcardiac muscle was examined by using a male guinea pig having a weightof 300 to 500 g. Namely, a right atrium was extirpated from a maleguinea pig and perfused with a Krebs-Henseleit solution to count itsspontaneous contractions with a cardiotachometer. The cologarithm of theconcentration of a test compound at which the heart rate was reduced by30% is shown in Table 1.

                  TABLE 1(I)                                                      ______________________________________                                        Effect upon cardiac muscle                                                    extirpated from guinea pig                                                    Test compound   -log EC.sub.30                                                ______________________________________                                        Compound A      6.3                                                           Compound B      5.9                                                           Compound C      6.0                                                           Compound D      6.8                                                           Compound E      6.6                                                           Compound F      6.1                                                           Compound G      6.1                                                           Compound H      5.5                                                           ______________________________________                                    

                  TABLE 1(II)                                                     ______________________________________                                        test compound   -log EC30                                                     ______________________________________                                        compound      A     6.6                                                                     B     6.8                                                                     C     6.0                                                                     D     6.1                                                                     E     6.3                                                       ______________________________________                                    

                  TABLE 1(III)                                                    ______________________________________                                        test compound   -log EC30                                                     ______________________________________                                        compound      A     6.4                                                                     B     6.5                                                                     C     6.2                                                                     E     5.7                                                       ______________________________________                                    

Experimental Example 2 Heart Rate Lowering and Coronary BloodflowIncreasing Effects Upon Anesthetized Thoracotomized Dog

The chest of a grown-up mongrel was opened under enflurane inhalationanesthesia. The blood flow of the coronary artery was determined bysetting a probe of an electromagnetic bloodflowmeter at its leftcircumflexbranch, while the heart rate was determined by triggering thewave form of the pressure in its left ventricle and counting it with atachometer.

The intravenous administration of a test compound (in a dose of 0.3 mgper kg of the weight of the anesthetized mongrel) was carried out byusing a catheter inserted into its femoral artery.

The effect of increasing the bloodflow of the circumflex branch of theleft coronary artery or the heart rate lowering effect was evaluatedbased on the difference between the bloodflow or the heart rate afterthe administration and that before the administration according to thefollowing criteria. The results are shown in Table 2 by a symbol (+).

                  TABLE 2(I)                                                      ______________________________________                                        Heart rate lowering and coronary                                              bloodflow increasing effects on                                               anesthetized thoracotomized dog                                               Test compound                                                                           Heart rate (HR)                                                                            Coronary bloodflow (CBF)                               ______________________________________                                        Compound A                                                                              +++          +                                                      Compound B                                                                              ++           +++                                                    Compound C                                                                              +            +++                                                    Compound I                                                                              ±         +++                                                    Compound J                                                                              +            +                                                      Compound K                                                                              ++           +                                                      Compound L                                                                              +            +                                                      Compound M                                                                              +            +                                                      ______________________________________                                    

                  TABLE 2(II)                                                     ______________________________________                                        test compound  heart rate (HR)                                                ______________________________________                                        compound     A     ++                                                                      B     +++                                                                     D     +++                                                                     F     +++                                                                     G     ++                                                                      H     ++                                                                      I     +                                                                       J     +                                                          ______________________________________                                    

                  TABLE 2(III)                                                    ______________________________________                                                     heart rate                                                                              coronary                                               test compound                                                                              (HR)      bloodflow (CBF)                                        ______________________________________                                        compound                                                                              A        +++       ±                                                       B        +         +                                                          D        ++        +                                                  ______________________________________                                    

                  TABLE 3                                                         ______________________________________                                        Rate of reduction in HR                                                                         Rate of increase in CBF                                     ______________________________________                                        ±    0%            ±    0%                                              +        1-10%        +        1-100%                                         ++      11-20%        ++      101-200%                                        +++     21-30%        +++     201-300%                                        ______________________________________                                    

Experimental Example 3 Toxicity Test

The representative compounds of the present invention were examined byan ordinary acute toxicity test (intravenous injection) using a mouse toobtain the results shown in Table 4.

                  TABLE 4                                                         ______________________________________                                        Test compound  LD.sub.50 (mg/kg, iv)                                          ______________________________________                                        Compound A      92                                                            Compound B      81                                                            Compound C      92                                                            Compound I      77                                                            Compound J      77                                                            Compound L      92                                                            Compound M     120                                                            ______________________________________                                    

EXAMPLES OF THE COMPOUNDS

The invention will be below illustrated in reference to preparation ormanufacturing examples to produce starting materials for the compoundsof the invention and examples of the compounds of the invention I, IIand III. They are listed below.

    ______________________________________                                                        I         II      III                                         ______________________________________                                        preparation examples or                                                                       1-14      1-6     1-25                                        manufacturing examples                                                        examples or     1-36      1-120   1-20                                        working examples                                                              ______________________________________                                    

EXAMPLES OF THE COMPOUND I Preparative Example 14-(4-Methyl-1H-imidazol-1-yl)benzaldehyde ##STR43##

4.20 g of sodium hydride (a 60% suspension thereof in a mineral oil) wassuspended in 150 ml of dimethylformamide to obtain a suspension. 8.62 gof 4-methylimidazol was added to the suspension at a room temperatureunder stirring in portions. After one hour, 12.4 g of4-fluorobenzaldehyde was added to the obtained mixture. The obtainedmixture was stirred for 4 hours and poured into ice-water. The obtainedmixture was extracted with chloroform. The extract was dried overanhydrous sodium sulfate and distilled under a reduced pressure toremove the solvent. The obtained residue was purified by silica gelcolumn chromatography (solvent: chloroform/methanol (50:1)) to obtain asolid product. This solid product was washed with ether to obtain 2.67 gof the title compound as a pale yellow powder (yield: 14%).

m.p. (°C.): 85.0 to 85.5

    ______________________________________                                        elemental analysis: as C.sub.11 H.sub.10 N.sub.2 O                                         C           H      N                                             ______________________________________                                        calculated (%)                                                                             70.95       5.41   15.05                                         found (%)    71.17       5.51   15.13                                         ______________________________________                                    

NMR(CDCl₃) δ; 2.29(3H,d,J=1.5 Hz), 7.04(1H,m), 7.3˜7.5(2H,m),7.7˜8.1(3H,m), 9.96(1H,s)

In a similar manner to the one described above, the following compoundwas prepared (yield: 55%).

4-(4-(1H)-Pyridon-1-yl)benzaldehyde ##STR44##

m.p. (°C.): 228 to 230

    ______________________________________                                        elemental analysis: as C.sub.12 H.sub.9 NO.sub.2                                           C           H      N                                             ______________________________________                                        calculated (%)                                                                             72.35       4.55   7.03                                          found (%)    72.58       4.64   7.04                                          ______________________________________                                    

NMR(DMSO-d₆) δ; 6.1˜6.4(2H,m), 7.6˜7.9(2H,m), 7.9˜8.2(4H,m), 10.05(1H,s)

Preparative Example 2 3-(1H-Imidazol-1-yl)benzaldehyde ##STR45##

A mixture comprising 9.25 g of 3-bromobenzaldehyde, 20.4 g of imidazole,0.31 g of copper powder and 50 ml of water was heated under reflux in anitrogen atmosphere for 3 days, followed by the addition of aqueousammonia. The obtained mixture was extracted with chloroform. The extractwas purified by silica gel column chromatography (solvent: methylenechloride/methanol) to obtain 4.61 g of the title compound as a paleyellow crystal (yield: 54%).

m.p. (°C.): 76.0 to 77.0

    ______________________________________                                        elemental analysis: as C.sub.10 H.sub.8 N.sub.2 O                                          C           H      N                                             ______________________________________                                        calculated (%)                                                                             69.75       4.68   16.27                                         found (%)    69.80       4.83   16.61                                         ______________________________________                                    

NMR(CDCl₃) δ; 7.20(1H,bs), 7.31(1H,m), 7.5˜7.7(2H,m), 7.7˜8.0(3H,m),10.02(1H,s)

Preparative Example 3 4-(4-Pyridyl)benzaldehyde ##STR46##

A solution of 6.93 g of 4-bromobenzaldehyde dimethyl acetal in 40 ml oftetrahydrofuran was dropwise added to a mixture comprising 0.80 g ofmagnesium powder, a catalytic amount of iodine and 10 ml oftetrahydrofuran under stirring at a temperature in the bulk of 40° to50° C. in a nitrogen atmosphere to prepare a Grignard reagent. ThisGrignard reagent was dropwise added to a solution of 4.46 g of4-bromopyridine and 0.4 g of bis(1,3-diphenylphosphinopropane)nickel(II) chloride in 100 ml of tetrahydrofuran at a room temperature in anitrogen atmosphere. The obtained mixture was refluxed for 4 hours andallowed to cool to a room temperature, followed by the addition ofwater. The obtained mixture was distilled to remove the tetrahydrofuranEthyl acetate was added to the residue. The obtained mixture wasextracted with dilute hydrochloric acid thrice. The extracts werecombined, allowed to stand for a short time, made alkaline withconcentrated aqueous ammonia and extracted with chloroform. The extractwas dried over anhydrous magnesium sulfate and distilled to remove thesolvent. The residue was purified by silica gel column chromatography(solvent: chloroform/methanol) to obtain 3.28 g of the title compound asa pale yellow crystal (yield: 64%).

m.p. (°C.): 89.5 to 90

    ______________________________________                                        elemental analysis: as C.sub.12 H.sub.9 NO                                                 C           H      N                                             ______________________________________                                        calculated (%)                                                                             78.67       4.95   7.65                                          found (%)    78.77       5.12   7.57                                          ______________________________________                                    

NMR(CDCl₃) δ; 7.50˜7.62(2H,m), 7.75˜7.93(2H,m), 7.96˜8.16(2H,m),8.70˜8.84(2H,m), 10.14(1H,s)

In a similar manner to the one described in Preparative Example 3, thefollowing compounds were prepared:

4-(3-Pyridyl)benzaldehyde ##STR47##

m.p. (°C.): 53.5 to 54.5

    ______________________________________                                        elemental analysis: as C.sub.12 H.sub.9 NO                                                 C           H      N                                             ______________________________________                                        calculated (%)                                                                             78.67       4.95   7.65                                          found (%)    78.57       5.06   7.56                                          ______________________________________                                    

NMR(CDCl₃) δ; 7.44(1H, ddd,J=7.2 Hz, 4.7 Hz, 1.0 Hz), 7.6-8.2(5H,m),8.75(1H,m), 8.94(1H,m), 10.12(1H,s)

4-(2-Pyridyl)benzaldehyde ##STR48##

m.p (°C.): 48.0 to 48.5

    ______________________________________                                        elemental analysis: C.sub.12 H.sub.9 NO                                                    C           H      N                                             ______________________________________                                        calculated (%)                                                                             78.67       4.95   7.65                                          found (%)    78.50       5.08   7.57                                          ______________________________________                                    

NMR(CDCl₃) δ; 7.22(1H,m), 7.8˜7.5(2H,m), 7.90(2H,d,J=8.3 Hz),8.08)2H,d,J=8.3 Hz), 8.65(1H,d,J=4.4 Hz), 9.98(1H,s)

4-(Imidazo[1,2-a]pyridin-6-yl)benzaldehyde ##STR49##

m.p. (°C.): 138.5 to 139.5

    ______________________________________                                        elemental analysis: C.sub.14 H.sub.10 N.sub.2 O                                            C           H      N                                             ______________________________________                                        calculated (%)                                                                             75.67       4.51   12.61                                         found (%)    75.58       4.67   12.68                                         ______________________________________                                    

NMR(CDCl₃) δ; 7.42(1H,dd,J=9.0 Hz, 2.5 Hz), 7.55˜7.80(5H,m),7.84˜8.04(2H,m), 8.15(1H,m), 9.98)1H,s)

Preparative Example 4 (E)-4-[4-(1H-Imidazol-1-yl)phenyl]-3-butenoic acid##STR50##

5.45 g of 4-(1H-imidazol-1-yl)benzaldehyde and 12.93 g ofβ-carboxyethyltriphenylphosphonium chloride were suspended in 70 ml oftetrahydrofuran. The obtained suspension was cooled to -50° C. andvigorously stirred. 30 ml of a solution of 7.83 g of potassiumt-butoxide in tetrahydrofuran was gradually added dropwise to theresulting suspension. The temperature of the obtained mixture wasgradually raised to 0° C. After one hour, ice-water was added to themixture. The obtained mixture was washed with ether. The pH of theaqueous layer was adjusted with concentrated hydrochloric acid to about4 to precipitate a solid. This solid was recovered by filtration andwashed with water and methanol to obtain 5.44 g of the title compound asa pale yellow powder (yield: 75%).

m.p. (°C.): 212 to 213.5

    ______________________________________                                        elemental analysis: as C.sub.13 H.sub.12 N.sub.2 O.sub.2                                   C           H      N                                             ______________________________________                                        calculated (%)                                                                             68.41       5.30   12.27                                         found (%)    68.51       5.42   12.08                                         ______________________________________                                    

NMR(DMSO-d₆) δ; 3.21(2H,d,J=5.7 Hz), 6.33(1H,dt,J=5.7 Hz, 15.8 Hz),6.57(1H,d,J=15.8 Hz), 7.10(1H,s), 7.3˜7.7(4H,m), 7.72(1H,s), 8.25(1H,s)

In a similar manner to the one described above, the following compoundswere prepared:

(E)-4-[3-(1H-Imidazol-1-yl)phenyl]-3-butenoic acid ##STR51##

m.p (°C.): 148.5 to 150.0

    ______________________________________                                        elemental analysis: as C.sub.13 H.sub.12 N.sub.2 O.sub.2                                   C           H      N                                             ______________________________________                                        calculated (%)                                                                             68.41       5.30   12.27                                         found (%)    68.23       5.39   12.34                                         ______________________________________                                    

NMR(DMSO-d₆) δ; 3.22(2H,d,J=5.4 Hz), 6.4˜6.6)2H,m), 7.07(1H,s),7.3˜7.6(3H,m), 7.66(1H,s), 7.73(1H,s), 8.24(1H,s)

(E)-4-[4-(2-Methyl-1H-imidazol-1-yl)phenyl]-3-butenoic acid ##STR52##

m.p. (°C.): 237 to 240 (dec.)

    ______________________________________                                        elemental analysis: as C.sub.14 H.sub.14 N.sub.2 O.sub.2                                   C           H      N                                             ______________________________________                                        calculated (%)                                                                             69.40       5.82   11.57                                         found (%)    69.57       6.05   11.45                                         ______________________________________                                    

NMR(DMSO-d₆) δ; 2.30(3H,d,J=0.9 Hz), 3.22(2H,d,J=6.2 Hz),6.37(1H,dt,J=6.2 Hz, 16.3 Hz), 6.61(1H,d,J=16.3 Hz), 6.92(1H,m),7.25(1H,m), 7.3˜7.4(2H,m), 7.4˜7.6(2H,m)

(E) -(4-Methyl-1H-imidazol-1-yl)phenyl]-3-butenoic acid ##STR53##

m.p. (°C.): 196 to 198

    ______________________________________                                        elemental analysis: as C.sub.14 H.sub.14 N.sub.2 O.sub.2                                   C           H      N                                             ______________________________________                                        calculated (%)                                                                             69.40       5.82   11.57                                         found (%)    69.64       5.87   11.54                                         ______________________________________                                    

NMR(DMSO-d₆) δ; 2.17(3H,s), 3.21(2H,d,J=6.2 Hz), 6.31(1H,dt,J=6.2 Hz,16.3 Hz), 6.55(1H,d,J=16.3 Hz), 7.41(1H,d,J=0.9 Hz), 7.52(4H,s),8.13(1H,d,J=0.9 Hz)

(E)-4-[4-(1H-Pyrazol-1-yl)phenyl]-3-butenoic acid ##STR54##

m.p. (°C.): 140 to 142

    ______________________________________                                        elemental analysis: as C.sub.13 H.sub.12 N.sub.2 O.sub.2                                   C           H      N                                             ______________________________________                                        calculated (%)                                                                             68.41       5.30   12.27                                         found (%)    68.30       5.45   12.41                                         ______________________________________                                    

NMR(CDCl₃) δ; 3.20(2H,d,J=7 Hz), 6.04˜6.60(3H,m), 7.2˜8.1(6H,m)

(E)-4-[4-(1,2,4-Triazol-1-yl)phenyl]-3-butenoic acid ##STR55##

m.p. (°C.): 217 to 218.5

    ______________________________________                                        elemental analysis: as C.sub.12 H.sub.11 N.sub.3 O.sub.2                                   C           H      N                                             ______________________________________                                        calculated (%)                                                                             62.87       4.84   18.33                                         found (%)    63.07       4.95   18.34                                         ______________________________________                                    

NMR(DMSO-d₆) δ; 3.23(2H,d,J=5.7 Hz), 6.36(1H,dt,J=5.7 Hz, 15.8 Hz),6.60(1H,d,J=15.8 Hz), 7.5˜7.7(2H,m), 7.7˜7.9(2H,m), 8.21(1H,s),9.28(1H,s), 12.35(1H,br)

(E1H)-4-[4-(1H-Pyrrol-1-yl)phenyl]-3-butenoic acid ##STR56##

m.p. (°C.): 191.0 to 192.0

    ______________________________________                                        elemental analysis: as C.sub.14 H.sub.13 NO.sub.2                                          C           H      N                                             ______________________________________                                        calculated (%)                                                                             73.99       5.77   6.16                                          found (%)    74.30       5.93   6.10                                          ______________________________________                                    

NMR(CDCl₃) δ; 3.17(2H,d,J=5.8 Hz), 6.04˜6.62(4H,m), 7.30(2H,m),7.44(4H,s)

(E)-4-[4-1H(3-Pyridyl)phenyl]-3-butenoic acid ##STR57##

m.p (°C.): 205.5 to 206.0

    ______________________________________                                        elemental analysis: as C.sub.15 H.sub.13 NO.sub.2                                          C           H      N                                             ______________________________________                                        calculated (%)                                                                             75.30       5.48   5.85                                          found (%)    75.42       5.64   5.80                                          ______________________________________                                    

NMR(DMSO-d₆) δ; 3.20(2H,d,J=5.4 Hz), 6.40(1H,dt,J=15.5 Hz, 5.4 Hz),6.50(1H,d,J=15.5 Hz), 7.4(1H,m), 7.50(2H,d,J=8.3 Hz), 7.66(2H,d,J=8.3Hz), 8.13(1H,d,J=7.2 Hz), 8.5(1H,bs), 8.8(1H,bs)

(E)-4-[4-(2-Pyridyl)phenyl]-3-butenoic acid ##STR58##

m.p. (°C.): 155.0 to 156.0

    ______________________________________                                        elemental analysis: as C.sub.15 H.sub.13 NO.sub.2                                          C           H      N                                             ______________________________________                                        calculated (%)                                                                             75.30       5.48   5.85                                          found (%)    74.95       5.44   5.72                                          ______________________________________                                    

NMR(DMSO-d₆) δ; 3.25(2H,d,J=5.7 Hz), 6.45(1H,dt,J=15.8 Hz, 5.7 Hz),6.58(1H,d,J=15.8 Hz), 7.30˜7.50(1H,m), 7.58(2H,d,J=8.4 Hz),7.80-8.00(2H,m), 8.08(2H,d,J=8.4 Hz), 8.65(1H,m)

(E)-4-[4-(4-Pyridyl)phenyl]-3-butenoic acid ##STR59##

m.p. (°C.): 209.5 to 211.0

    ______________________________________                                        elemental analysis: as C.sub.15 H.sub.13 NO.sub.2                                          C           H      N                                             ______________________________________                                        calculated (%)                                                                             75.30       5.48   5.85                                          found (%)    75.23       5.59   5.78                                          ______________________________________                                    

H-NMR(DMSO-d₆) δ; 3.25(2H,d,J=6.1 Hz), 6.48(1H,dt,J=15.5 Hz, 6.1Hz),6.60(1H,d,J=15.5 Hz), 7.4˜8.0(6H,m), 8.7(2H,m)

(E)-4-[4(1H)-Pyridon-1-yl)phenyl]-3-butenoic acid ##STR60##

m.p. (°C.): 275 (dec.)

    ______________________________________                                        elemental analysis: as C.sub.15 H.sub.13 NO.sub.3                                          C           H      N                                             ______________________________________                                        calculated (%)                                                                             70.58       5.13   5.49                                          found (%)    70.55       5.25   5.46                                          ______________________________________                                    

H-NMR(DMSO-d₆) δ; 3.2(1H,d,J=5.6 Hz), 6.1˜6.3(2H,m), 6.36(1H,dt,J=5.6Hz, 16.3 Hz), 6.60(1H,d,J=16.3 Hz), 7.3˜7.7(4H,m), 7.8˜8.1(2H,m)

(E)-4-[4-(Imidazo[1,2-a]pyridin-6-yl)phenyl]-3-butenoic acid ##STR61##

m.p. (°C.): 254 to 260.0 (dec.)

    ______________________________________                                        elemental analysis: as C.sub.16 H.sub.14 N.sub.2 O.sub.2                                   C           H      N                                             ______________________________________                                        calculated (%)                                                                             73.37       5.07   10.07                                         found (%)    73.15       5.16   10.00                                         ______________________________________                                    

H-NMR(DMSO-d₆) δ; 3.23(2H,d,J=5.8 Hz), 6.47(1H,dt,J=15.5 Hz, 5.8 Hz),6.57(1H,d,J=15.5 Hz), 7.4˜7.8(7H,m), 7.99(1H,s), 8.98(1H,s)

Preparative Example 5N-[3-{N'-Methyl-N'-(2-(3,5-dimethoxyphenyl)ethyl)amino}propyl]phthalimide##STR62##

A mixture comprising 9.30 g ofN-methyl-(2-(3,5-dimethoxyphenyl)ethyl)amine, 13.4 g ofN-(3-bromopropyl)phthalimide, 7.2 g of potassium carbonate and 100 ml ofdimethylformamide was stirred at 80° C. for 8 hours. After thecompletion of the reaction, the reaction mixture was filtered to removean inorganic matter. The filtrate was distilled to remove thedimethylformamide. Ethyl acetate was added to the residue. The obtainedmixture was washed with water and extracted with dilute hydrochloricacid thrice. The extracts were combined, neutralized with concentratedaqueous ammonia and extracted with chloroform. The extract was driedover anhydrous magnesium sulfate and filtered. The filtrate wasdistilled to remove the solvent. The residue was purified by silica gelcolumn chromatography (solvent: chloroform/methanol) to obtain 12.4 g ofthe title compound as a pale yellow oil (yield: 64%).

NMR(CDCl₃) δ; 1.6˜2.0(2H,m), 2.26(3H,s), 2.3˜2.7(6H,m), 3.5˜3.8(2H,m),3.75(6H,s), 6.20˜6.36(3H,m), 7.50˜7.90(4H,m)

Preparative Example 6N-Methyl-N-(2-(3,5-dimethoxyphenyl)ethyl)-1,3-propanediamine ##STR63##

9.24 g of theN-[3-(N'-methyl-N'-(2-(3,5-dimethoxyphenyl)ethyl)amino)propyl'phthalimideprepared in Preparative Example 5 and 4 ml of hydrazine monohydrate weredissolved in 100 ml of ethanol to obtain a solution This solution washeated under reflux for 2 hours, cooled to a room temperature andfiltered to remove generated precipitates The filtrate was distilled toremove the ethanol. Chloroform was added to the residue. The obtainedmixture was washed with an aqueous solution of caustic soda twice andwith a saturated aqueous solution of common salt once, dried overanhydrous magnesium sulfate and distilled to remove the solvent. 5.81 gof the title compound was obtained as a pale yellow oil (yield: 96%).This oil was used in the following reaction without any additionalpurification.

NMR(CDCl₃) δ; 1.4˜1.8(2H,m), 1.22(2H,bs), 2.28(3H,s), 2.3˜2.8(8H,m),3.75(6H,s), 6.2˜6.4(3H,m)

In a similar manner to the one described above, the following compoundswere prepared:

N-Methyl-N-[2-(3,4-diethoxyphenyl)ethyl]-1,3-propanediamine ##STR64##

yellow oil

NMR(CDCl₃) δ; 1.21(2H,s), 1.3˜1.8(8H,m), 2.28(3H,s), 2.3˜2.9(8H,m),4.04(2H,q,J=7.0 Hz), 4.07(2H,q,J=7.0 Hz), 6.6˜7.0(3H,m).

N-Methyl-N-[2-(3,4-ethylenedioxyphenyl)ethyl]-1,3-propanediamine##STR65##

yellow oil

NMR(CDCl₃) δ; 1.4˜2.1(4H,m), 2.27(3H,s), 2.3˜2.9(8H,m), 4.22(4H,s),6.4˜6.8(3H,m)

N-Methyl-N-[2-(4-pyridyl)ethyl]-1,3-propanediamine ##STR66##

yellow oil

NMR(CDCl₃) δ; 1.4˜1.8(2H,m), 2.0˜2.9(13H,m), 6.9˜7.2(2H,m),8.3˜8.6(2H,m)

N-Methyl-N-(6 7-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-propanediamine ##STR67##

yellow oil

NMR(CDCl₃) δ;

1.4˜2.2(6H,m), 2.32(3H,s), 2.4˜2.9(9H,m), 3.83(6H,s), 6.56(2H,s)

N-Methyl-N-(2-phenylethyl)-1,3-propanediamine ##STR68##

yellow oil

NMR(CDCl₃) δ; 1.5˜1.8(4H,m), 2.24(3H,s), 2.3˜2.9(8H,m), 6.9˜7.3(5H,m)

N-Methyl-N-[2-(3,4-methylenedioxyphenyl)ethyl]-1,3-propanediamine##STR69##

yellow oil

NMR(CDCl₃) δ; 1.4˜1.8(4H,m), 2.14(3H,s), 2.1˜2.8(8H,m), 5.90(2H,s),6.4˜6.7(3H,m)

N-Methyl-N-[2-(3-methoxyphenyl)ethyl]-1,3-propanediamine ##STR70##

yellow oil

NMR(CDCl₃) δ;

1.30(2H,s), 1.4˜1.8(2H,m), 2.14(3H,s), 2.2˜2.9(8H,m), 3.84(3H,s),6.5˜6.8(3H,m), 6.9˜7.2(1H,m)

N-Allyl-N-[2-(4-methoxyphenyl)ethyl]-1,3-propanediamine ##STR71##

yellow oil

NMR(CDCl₃) δ; 1.40(2H,s), 1.4˜1.8(2H,m), 2.4˜2.8(8H,m), 3.10(2H,d,J=7Hz), 3.74(3H,s), 4.96˜5.30(2H,m), 5.76˜6.02(1H,m). 6.6(2H,d,J=10 Hz),7.0(2H,d,J=10 Hz)

Preparative Example 8N-Cyclopentyl-N'-methyl-N'-[2-(3,4-dimethoxyphenyl)ethyl]-1,3-propanediamin##STR72##

500 mg of N-methyl-N-[2-(3 4-dimethoxyphenyl)-ethyl]-1,3-propanediamineand 0.21 ml of cyclopentanone were dissolved in 5 ml of ethanol,followed by the addition of 10 mg of platinum oxide to carry outhydrogenation at a room temperature under 1 atm for 6 hours. Thereaction mixture was filtered to remove the catalyst. The filtrate wasconcentrated under a reduced pressure to obtain 660 mg of the titlecompound as a yellow oil (yield: 100%).

NMR(CDCl₃) δ; 1.1˜2.1(10H,m), 2.2˜2.9(12H,m), 2.9˜3.2(1H,m), 3.84(3H,s),3.86(3H,s), 6.6˜6.9(3H,m)

Preparative Example 9 N-[2-(3,4-Dimethoxyphenyl)ethyl]homopiperazine##STR73##

32 27 g of homopiperazine, 13.2 g of 2-(3,4-dimethoxyphenyl)ethylchloride and 71.3 g of potassium carbonate were added to 500 ml ofacetonitrile. The obtained mixture was heated under reflux for 20 hours,cooled and filtered The filtrate was concentrated under a reducedpressure to obtain a residue. This residue was extracted with etherthrice. The extracts were combined, dried over anhydrous sodium sulfateand filtered The filtrate was concentrated under a reduced pressure Theobtained residue was purified by silica gel column chromatography(solvent: chloroform/methanol/isopropylamine (100:10:1)) to obtain 13.40g of the title compound as a yellow oil (yield: 77%).

NMR(CDCl₃) δ; 1.83˜1.98(2H,m), 2.39˜3.11(13H,m), 3.83(3H,s), 3.84(3H,s),6.55˜6.83(3H,m)

Preparative Example 10N,N'-Dimethyl-N-[2-(3,4-dimethoxyphenyl)ethyl]-1,3-propanediamine##STR74##

3.0 g of N-methyl-N-2-(3,4-dimethoxyphenyl)-ethyl-1,3-propanediamine wasdissolved in a mixture comprising 1.8 ml of triethylamine and 100 ml ofdichloromethane, followed by stirring under cooling with ice-water. 1.0ml of methyl chloroformate was dropwise added to the obtained solution.The obtained mixture was stirred for several minutes and distilled toremove the dichloromethane. The residue was extracted with ethylacetate. The extract was dried over anhydrous magnesium sulfate anddistilled to remove the solvent. Thus, 2.84 g of a methylcarbamate wasobtained. This methylcarbamate was dissolved in 100 ml oftetrahydrofuran to obtain a solution. This solution was dropwise addedto a solution of 0.54 g of lithium aluminum hydride in 100 ml oftetrahydrofuran. The obtained mixture was heated under reflux for 2hours and cooled with ice. 0.5 ml of water, 0.5 ml of a 15% aqueoussolution of caustic soda and 1.5 ml of water were added to the resultingmixture successively. The obtained mixture was stirred at a roomtemperature for 30 minutes, followed by the addition of magnesiumsulfate. The obtained mixture was filtered and the filtrate wasdistilled to remove the solvent. Thus, 2.30 g of the title compound wasobtained as a light brown oil (yield: 72%).

NMR(CDCl₃) δ;

1.44(1H,bs), 1.5˜1.9(2H,m), 2.28(3H,s), 2.39(3H,s), 2.4˜2.9(8H,m),3.83(3H,s), 3.85(3H,s), 6.6˜6.9(3H,m)

Preparative Example 11N-Methyl-N-(4-(tert-butyldimethylsiloxy)-butan-2-yl)-[2-(3,4-dimethoxyphenyl)ethyl]amine##STR75##

2.39 g of methanesulfonyl chloride was gradually added to 50 ml of asolution of 3.55 g of 4-(tert-butyldimethylsiloxy)butan-2-ol and 2.1 gof triethylamine in ether under cooling with ice. After 30 minutes,water was added to the obtained mixture. The obtained mixture wasextracted with ether. The extract was dried over anhydrous sodiumsulfate, filtered and distilled to remove the ether. The residue wasdissolved in 50 ml of acetonitrile, followed by the addition of 6.74 gof N-methyl-[2-(3,4-dimethoxyphenyl)ethyl]amine hydroiodide and 7.7 g ofpotassium carbonate. The obtained mixture was heated under reflux for 12hours, cooled and filtered to remove generated crystalline precipitates.The filtrate was concentrated under a reduced pressure and extractedwith ether thrice. The ether layers were combined, washed with anaqueous solution of common salt, dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated under a reduced pressure andpurified by silica gel column chromatography (solvent:chloroform/methanol (100:1)) to obtain 2.34 g of the title compound as ayellow oil (yield: 35%).

NMR(CDCl₃) δ; 0.05(6H,s), 0.88(9H,s), 0.94(3H,d,J=6.1 Hz),1.26˜1.95(2H,m), 2.24(3H,s), 2.36˜3.03(5H,m), 3.58(2H,t,J=5.8 Hz),3.81(3H,s), 3.83(3H,s), 6.55˜6.80(3H,m)

Preparative Example 12N-[3-((N'-Methyl-N'-2-(3,4-dimethoxyphenyl)ethyl)amino)butyl]phthalimide##STR76##

N-Methyl-N-(4-(t-butyldimethylsiloxy)-butan-2-yl)-[2-(3,4-dimethoxyphenyl)ethyl]aminewas dissolved in 12 ml of tetrahydrofuran to obtain a solution. 12 ml ofa solution (1 mmol/ml) of tetra-n-butylammonium fluoride intetrahydrofuran was gradually added dropwise to the above solution at aroom temperature. The obtained mixture was stirred at a room temperaturefor 3 hours and distilled to remove the solvent. The residue wasextracted with ether thrice. The extracts were combined, dried overanhydrous sodium sulfate and concentrated under a reduced pressure. Theresidue was dissolved in 12 ml of tetrahydrofuran, followed by theaddition of 900 mg of phthalimide and 1.61 g of triphenylphosphine. 1.07g of diethyl azodicarboxylate was gradually added to the obtainedmixture at a room temperature. The obtained mixture was stirredovernight and distilled to remove the solvent. The residue was madeacidic with 0.5 N hydrochloric acid and washed with ether. The aqueouslayer was made basic with lithium hydroxide and extracted with ethylacetate. The extract was dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated under a reduced pressure andpurified by silica gel column chromatography (solvent:chloroform/methanol (100:1)) to obtain 2.19 g of the title compound as ayellow oil (yield: 90%).

NMR(CDCl₃) δ; 0.96(3H,d,J=6.5 Hz), 1.43˜2.01(2H,m), 2.27(3H,s),2.44˜2.93(5H,m), 3.60˜3.81(2H,m), 3.91(3H,s), 3.85(3H,s), 6.80(3H,m),7.57˜7.97(4H,m)

Preparative Example 133-[N-Methyl-N-(2-(3,4-dimethoxyphenyl)ethyl)amino]butylamine ##STR77##

46.36 g ofN-[3-(N'-methyl-2-(3,4-dimethoxyphenyl)ethyl)amino-3-methylpropyl]phthalimideand 7.03 g of hydrazine monohydrate were added to 500 ml of ethanol. Theobtained mixture was heated under reflux for 2 hours, cooled andfiltered to remove generated white precipitates. The filtrate wasconcentrated under a reduced pressure to obtain a residue. 200 ml of a10% aqueous solution of sodium hydroxide was added to the residue,followed by the extraction with chloroform thrice. The extracts werecombined, washed with a saturated aqueous solution of common salt, driedover anhydrous sodium sulfate and concentrated under a reduced pressureto obtain 26.88 g of the title compound as a yellow oil (yield: 86%).

NMR(CDCl₃) δ; 0.93(3H,d,J=6.3 Hz), 0.93˜1.82(4H,m), 2.12(3H,s),2.24˜2.93(7H,m), 3.78(3H,s), 3.83(3H,s), 6.54˜6.84(3H,m)

Preparative Example 14N-Methyl-N-[2-(3,4-dimethoxyphenyl)ethyl]-2-methyl-1,3-propanediamine##STR78##

A mixture comprising 6.5 g of N-methyl-2-(3,4-dimethoxyphenyl)ethylaminehydroiodide, 1.6 g of methacrylonitrile and 2.4 g of triethylamine washeated at about 70° C. for 2.5 hours and cooled, followed by theaddition of dichloromethane. The obtained mixture was washed with water,dried over magnesium sulfate and distilled to remove the solvent Theresidue was purified by silica gel column chromatography (solvent:dichloromethane/ethanol (100:1)) to obtain 2.1 g of3-[N-methyl-N-(2-(3,4-dimethoxyphenyl)ethyl)amino-3-2-methylpropionitrile.

NMR(CDCl₃) δ; 1.24(3H,d,J=7 Hz), 2.30(3H,s), 2.3˜2.8(7H,m), 3.8(6H,s),6.5˜6.8(3H,m)

2.1 g of the above nitrile and 0 2 ml of concentrated hydrochloric acidwere dissolved in 30 ml of ethanol, followed by the addition of 0.2 g ofplatinum oxide to carry out hydrogenation under a hydrogen pressure of2.1 kg/cm². The reaction mixture was filtered to remove the catalyst.The filtrate was distilled under a reduced pressure to remove theethanol. The residue was made alkaline with a dilute solution of causticsoda. The aqueous layer was extracted with dichloromethane. The extractwas washed with water, dried over magnesium sulfate and distilled undera reduced pressure to obtain 1.98 g of the title compound as a paleyellow oil (yield: 38%).

NMR(CDCl₃) δ; 0.90(3H,d,J=7 Hz), 1.36(2H,s), 1.50˜1.80(1H,m),2.10(3H,s), 2.1˜2.8(8H,m), 3.80(3H,s), 3.84(3H,s), 6.6˜6.8(3H,m).

Example 1(E)-N-[3-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(1H-imidazol-1-yl)phenyl)-3-butenamide##STR79##

62.1 g of (E)-4-C4-(1H-imidazol-1-yl)phenyl]-3-butenoic acid and 36.8 gof N-hydroxybenzotriazole were added to 800 ml of acetonitrilecontaining 50% of water, followed by stirring under cooling withice-water. 56.2 g of N,N'-dicyclohexylcarbodiimide was added to theobtained mixture in portions. The obtained mixture was stirred for 2hours, followed by the dropwise addition of 65.4 g ofN-methyl-N-[2-(3,4-dimethoxyphenyl)ethyl]-1,3-propanediamine. After thecompletion of the above dropwise addition, the obtained mixture wasstirred at a room temperature for 3 days and filtered to removegenerated precipitates. The filtrate was sufficiently washed with ethylacetate and extracted with dilute hydrochloric acid. The pH of theaqueous layer was adjusted with potassium carbonate to 9. The resultinglayer was extracted with ethyl acetate The extract was dried overanhydrous sodium sulfate, concentrated under a reduced pressure andpurified by silica gel column chromatography (solvent:chloroform/methanol/concentrated aqueous ammonia (1000:100:2)) to obtain61.7 g of the title compound as a pale yellow oil (yield: 52%).

NMR(CDCl₃) δ; 1.5˜1.8(2H,m), 2.20(3H,s), 2.3˜2.8(6H,m), 3.02(2H,d,J=6.5Hz), 3.2˜3.5(2H,m), 3.84(3H,s), 3.86(3H,s), 6.20(1H,dt,J=6.1 Hz,15.8Hz), 7.46(1H,d,J=15.8 Hz), 6.5˜6.8 (3H,m), 7.1∫7.5(7H,m), 7.77(1H,s)

Example 2(E)-N-[3-((N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(1H-imidazol-1-yl)phenyl)-3-butenamide##STR80##

60 g of (E)-4-E4-(1H-imidazol-1-yl)phenyl]-3-butenoic acid was added to1000 ml of acetonitrile containing 50% of water. The obtained mixturewas stirred under cooling with ice-water, followed by the addition of57.0 g of N,N'-dicyclohexylcarbodiimide and 37.3 g ofN-hydroxybenzotriazole. The obtained mixture was stirred for about 4hours to obtain a solution. A solution of 66.3 g ofN-methyl-N-(2-(3,5-dimethoxyphenyl)ethyl)-1,3-propanediamine in about 60ml of acetonitrile was dropwise added to the above solution. Thetemperature of the obtained mixture was raised to a room temperature.The resulting mixture was stirred overnight, heated to a temperature of30° to 40° C. and stirred for about 4 hours. After the completion of thereaction, the reaction mixture was filtered to remove generatedprecipitates. The filtrate was distilled to remove the acetonitrile,followed by the addition of ethyl acetate. The obtained mixture wasextracted with dilute hydrochloric acid twice. The extracts werecombined, neutralized with concentrated aqueous ammonia and extractedwith chloroform. The extract was dried over anhydrous magnesium sulfateand distilled to remove the solvent, thus giving a yellow oil. Thisyellow oil was purified by silica gel column chromatography (solvent:chloroform/methanol/concentrated aqueous ammonia (100:10:0.2)) to obtain74 g of the title compound as a pale yellow oil (yield: 62%).

NMR(CDCl₃) δ; 1.5˜1.8(2H,m), 2.17(3H,s), 2.3˜2.5(6H,m), 3.01(2H,d,J=5.4Hz), 3.1˜3.5(2H,m), 3.72(6H,s), 6.0˜6.3(4H,m), 6.40(1H,d,J=15.5 Hz),7.1˜7.5(7H,m), 7.78(1H,s)

Dihydrochloride dihydrate of the above produced butenamide was preparedin the following way.

258.9 g of the above produced product was dissolved in 7770 ml ofacetone and 518 ml of water was added to the solution. The mixture wascooled with ice. 210 ml of an acetone solution of 100 ml of concentratedhydrochloric acid was added thereto dropwise and the mixture was stirredover one night. The precipitates obtained in the mixture was taken withfiltration and washed with 1 liter cf acetone. They were then dried at55 degree C. to obtain 270 g of the dihydrochloride dihydrate, beingwhite to light yellow powder, with a production yield of 90.1 %. Theproduct was found to show a heat-absorption peak around 100 degree Caccording to DSC. With reference to C27H34N4O3.2HCL.2H2O, results of Itselement analyses was:

    ______________________________________                                                  C             H      N                                              ______________________________________                                        calcd.    56.74         7.05   9.80                                           found     56.72         6.93   9.86                                           ______________________________________                                    

Example 3(E)-N-[3-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-(4-(1H-imidazol-1-yl)phenyl)-3-butenamide##STR81##

51.2 g of (E)-4-[4-(1H-imidazol-1-yl)phenyl]-3-butenoic acid and 27.24 gof N-hydroxybenzotriazole were dissolved in a mixture comprising 500 mlof water and 500 ml of acetonitrile, followed by the addition of 41.6 gof N,N'-dicyclohexylcarbodiimide. The obtained mixture was stirred at 0°C. for 30 minutes, followed by the slow stepwise addition of a solutionof the 3-(N-methyl-N-(2-(3,4-dimethoxyphenyl)ethyl)amino)butylamineprepared in Preparative Example 13 in 160 ml of acetonitrile. Theobtained mixture was stirred at a room temperature overnight, heated at40° C. for 2 hours, cooled and filtered. The filtrate was concentratedunder a reduced pressure The pH of the aqueous layer was adjusted to 3,followed by the addition of ethyl acetate. The obtained mixture wasshaken to remove the organic layer. The remaining aqueous layer was madealkaline with sodium hydroxide and extracted with ethyl acetate thrice.The ethyl acetate layers were combined, dried over sodium sulfate andconcentrated under a reduced pressure to obtain a residue. This residuewas purified by silica gel column chromatography (solvent:chloroform/methanol/concentrated aqueous ammonia (1000:100:2)) to obtain57.7 g of the title compound as a pale yellow oil (yield: 63%).

NMR(400 MHz, CDCl₃)(δ; 0.92(3H,d,J=6.2 Hz), 1.40˜1.65(2H,m), 2.18(3H,s),2.50˜2.70(4H,m), 2.75˜2.90(1H,m), 3.02(2H,d,J=7.0 Hz), 3.05˜3.20(1H,m),3.50˜3.60(1H,m), 3.83(3H,s), 3.85(3H,s), 6.30(1H,dt,J=7.0 Hz,16.1 Hz),6.47(1H,d,J=16.1 Hz), 6.62˜6.71(2H,m), 6.76(1H,d,J=8.1 Hz), 7.16(1H,bs),7.26(1H,m), 7.29(2H,d,J=8.4 Hz), 7.43(2H,d,J=8.4 Hz), 7.83(1H,bs)

Examples 4 to 36

The compounds described in Examples 4 to 37 were each prepared in asimilar manner to the one described in Example 1.

Namely, the compounds were each prepared by the same procedure as theone described in Example 1 except that the(E)-4-[4-(1H-imidazol-1-yl)phenyl]-3-butenoic acid was replaced by thecorresponding 4-substituted phenyl-3-butenoic acid and theN-methyl-N-[2-(3,4-dimethoxyphenyl)ethyl]-1,3-propanediamine wasreplaced by the corresponding substituted alkylenediamine.

Example 4(E)-N-[3-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-N-cyclopentyl-4-(4-(1H-imidazol-1-yl)phenyl)-3-butenamide##STR82##

NMR(CDCl₃) δ; 1.2˜2.0(10H,s), 2.30(3H,s), 2.3˜2.8(6H,m), 3.0˜3.4(5H,m),3.80(3H,s), 3.83(3H,s), 6.24(1H,dt,J=7.2 Hz,16.0 Hz), 6.46(1H,d,J=16.0Hz), 6.5˜6.8(3H,m), 7.1˜7.5(6H,m), 7.77(1H,s)

Example 5(E)-N-[3-((N'-(2-(4-Methoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(1H-imidazol-1-yl)phenyl)-3-butenamide##STR83##

NMR(CDCl₃) δ; 1.5˜1.8(2H,m), 2.22(3H,s), 2.3˜2.8(6H,m), 3.06(2H,d,J=5.7Hz), 3.1˜3.5(2H,m), 6.26(1H,dt,J=5.7 Hz,15.8 Hz), 6.51(1H,d,J=15.8 Hz),6.7˜7.1(3H,m), 7.1˜7.5(6H,m), 7.78(1H,s), 8.3˜8.5(2H,m)

Example 6(E)-N-Methyl-N-[3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(1H-imidazol-1-yl)phenyl)-3-butenamide##STR84##

NMR(400 MHz, DMSO-d₆, 150° C.) δ; 1.65˜1.75(2H,m), 2.29(3H,s),2.45(2H,m), 2.60˜2.7(2H,m), 2.70˜2.80(2H,m), 2.94(3H,bs),3.30(2H,dd,J=6.6 Hz,1.5 Hz), 3.33˜3.37(2H,m), 3.75(3H,s), 3.77(3H,s),6.37(1H,dt,J=16.1 Hz,6.6 Hz), 6.52(1H,dt,J=16.1 Hz,1.5 Hz),6.74(1H,dd,J=8.1 Hz,2.2 Hz), 6.83(1H,d,J=2.2 Hz), 6.84(1H,d,J=8.1 Hz),7.09(1H,bs), 7.46˜7.55(4H,m), 7.55˜7.57(1H,m), 8.05(1H,bs)

Example 7(E)-N-[3-((N'-(2-(3-Methoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(1H-imidazol-1yl)phenyl)-3-butenamide##STR85##

NMR(CDCl₃) δ; 1.5˜1.8(2H,m), 2.20(3H,s), 2.40˜2.81(6H,m),3.08(2H,d,J=6.8 Hz), 3.2˜3.5(2H,m), 3.76(3H,s), 6.23(1H,dt,J=6.8 Hz,16.2Hz), 6.48(1H,d,J=16.2 Hz), 6.64˜6.80(4H,m), 7.00˜7.48(7H,m), 7.80(1H,br)

Example 8(E)-N-[3-((N'-(2-(4-Methoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(1H-imidazol-1-yl)phenyl)-3butenamide##STR86##

NMR(CDCl₃) δ; 1.44˜1.80(2H,m), 2.20(3H,s), 2.30˜2.80(6H,m),3.0(2H,d,J=7.0 Hz), 3.16˜3.40(2H,m), 3.70(3H,s), 6.20(1H,dt,J=7.0Hz,16.0 Hz), 6.40(1H,d,J=16.0 Hz), 6.60˜7.5(11H,m), 7.72(1H,s)

Example 9(E)-N-[3-((N'-(2-Phenylethyl)-N'-methyl)amino)propyl]-4-(4-(1H-imidazol-1-yl)phenyl)-3-butenamide##STR87##

NMR(CDCl₃) δ; 1.5˜1.9(2H,m), 2.19(3H,s), 2.35˜2.90(6H,m),3.00(2H,d,J=7.2 Hz), 3.2˜3.5(2H,m), 6.20(1H,dt,J=7.2 Hz,16.2 Hz),6.43(1H, d,J=16.2 Hz), 6.75˜7.65(12H,m), 7.75(1H,br)

Example 10(E)-N-[3-((N'-(2-(3,4,5-Trimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(1H-imidazol-1-yl)phenyl)-3-butenamide##STR88##

NMR(CDCl₃) δ; 1.50˜1.84(2H,m), 2.20(3H,s), 2.34˜2.76(6H,m),3.04(2H,d,J=6.0 Hz), 3.16˜3.46(2H,m), 3.74(9H,s), 5.96˜6.56(4H,m),7.04˜7.48(7H,m), 7.72(1H,s)

Example 11(E)-N-[3-((N'-(2-(3,4-Diethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(1H-imidazol-1-yl)phenyl)-3-butenamide##STR89##

NMR(CDCl₃) δ; 1.40(3H,t,J=7.0 Hz), 1.41(3H,t,J=7.0 Hz), 1.5˜1.8(2H,m),2.21(3H,s), 2.3˜2.8(6H,m), 3.04(2H,d,J=5.7 Hz), 3.2˜3.5(2H,m),3.99(2H,q,J=7.0Hz), 4.00(2H,q,J=7.0 Hz), 6.18(1H,dt,J=5.7 Hz,15.5 Hz),6.44(1H,d,J=15.5 Hz), 6.5˜6.8(3H,m), 7.0˜7.5(7H,m), 7.75(1H,bs)

Example 12(E)-N-[3-((N'-(2-(2,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(1H-imidazol-1-yl)phenyl)-3-butenamide##STR90##

NMR(CDCl₃) δ; 1.50˜1.80(2H,m), 2.20(3H,s), 2.40˜2.80(6H,m),3.04(2H,d,J=5.7 Hz), 3.6˜3.44(2H,m), 3.64(3H,s), 3.68(3H,s),5.90˜6.52(2H,m), 6.52˜6.80(3H,m), 7.04˜7.60(7H,m), 7.72(1H,s)

Example 13(E)-N-[3-((N'-(2-(3,4-Methylenedioxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(1H-imidazol-1-yl)phenyl)-3-butenamide##STR91##

NMR(CDCl₃) δ; 1.45˜1.80(2H,m), 2.16(3H,s), 2.30˜2.70(6H,m),3.04(2H,d,J=5.4 Hz), 3.10˜3.40(2H,m), 5.80(2H,s), 6.0˜6.72(5H,m),7.04˜7.60(7H,m), 7.76(1H,s)

Example 14(E)-N-[3-((N'-(2-(3,4-Ethylenedioxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(1H-imidazol-1-yl)phenyl)-3-butenamide##STR92##

NMR(CDCl₃)67 ; 1.5˜1.8(2H,m), 2.18(3H,s), 2.3˜2.7(6H,m), 3.06(2H,d,J=6.2Hz), 3.2˜3.5(2H,m), 4.18(4H,s), 6.0˜6.8(5H,m), 7.0˜7.5(7H,m), 7.78(1H,s)

Example 15(E)-N-[3-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(3-(1H-imidazol-1-yl)phenyl)-3-butenamide##STR93##

NMR(CDCl₃) δ; 1.5˜1.8(2H,m), 2.21(3H,s), 2.3˜2.8(6H,m), 3.00(2H,d,J=6.1Hz), 3.1˜3.5(2H,m), (2H,m), 3.78(3H,s), 3.80(3H,s), 6.26(1H,dt,J=16.6Hz, 6.1 Hz), 6.38(1H,d,J=16.6 Hz), 6.5˜6.7(3H,m), 6.9˜7.2(7H,m),7.72(1H,bs)

Example 16(E)-N-[3-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-3-butenamide##STR94##

NMR(CDCl₃) δ; 1.5˜1.9(2H,m), 2.23(3H,s), 2.33(3H,s), 2.3˜2.8(6H,m),3.06(2H,d,J=5.7 Hz), 3.1˜3.5(2H,m), 3.82(3H,s), 3.85(3H,s),6.30(H,dt,J=5.7 Hz,15.4 Hz), 6.53(1H,d,J=15.4 Hz), 6.5˜6.8 (3H,m),6.95(1H,d,J=1.3 Hz), 7.00 (1H,d,J=1.3 Hz), 7.0˜7.2(2H,m), 7.2˜7.5(3H,m)

Example 17(E)-N-[3-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-N-cyclopentyl-4-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-3-butenamide##STR95##

NMR(CDCl₃) δ; 1.20-2.08(10H,m), 2.31(3H,s), 2.34(3H,s), 2.40˜2.87(6H,m),2.95˜3.40(5H,m), 3.81(3H,s), 3.84(3H,s), 6.20-6.50(2H,m),6.51˜6.80(3H,m), 6.81˜7.00(2H,m), 7.00˜7.20(2H,m), 7.30˜7.50(2H,m)

Example 18(E)-N-[3-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(4-methyl-1H-imidazol-1-yl)phenyl)-3-butenamide##STR96##

NMR(CDCl₃) δ; 1.5˜1.8(2H,m), 2.20(3H,s), 2.27(3H,s), 2.3˜2.8(6H,m),3.04(2H,d,J=5.7 Hz), 3.2˜3.5(2H,m), 3.82(3H,s), 3.84(3H,s),6.23(1H,dt,J=5.7 Hz,15.8 Hz), 6.49(1H,d,J=15.8 Hz), b 6.96(1H,d,J=0.9Hz), 7.1˜7.5(5H,m), 7.67(1H,d,J=0.9 Hz)

Example 19(E)-N-[3-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(3-pyridyl)phenyl)-3-butenamide##STR97##

NMR(CDCl₃) δ; 1.5˜1.7(2H,m), 2.18(3H,s), 2.3˜2.8(6H,m), 3.04(2H,d,J=5.4Hz), 3.2˜3.5(2H,m), 3.78(3H,s), 3.80(3H,s), 6.30(1H,dt,J=15.8 Hz, 5.4Hz), 6.44(1H,d,J=15.8 Hz), 6.5˜6.8(3H,m), 7.2˜7.5(6H,m),7.76(1H,dm,J=8.3 Hz), 8.50(1H,dd,J=5.4 Hz,2.5Hz), 8.76(1H,d,J=2.5 Hz)

Example 20(E)-N-[3-((N'-(2-(3,4,5-Trimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(3-pyridyl)phenyl)-3-butenamide##STR98##

NMR(CDCl₃) δ; 1.5-1.8(2H,m), 2.20(3H,s), 2.30˜2.70(6H,m),3.08(2H,d,J=5.4 Hz), 3.1˜3.5(2H,m), 3.78(9H,s), 6.30(2H,s),6.36(1H,dt,J=5.4 Hz, 15.8 Hz), 6.46(1H,d,J=1.58Hz), 7.1˜7.6(6H,m),7.75(1H,d,J=7.2 Hz), 8.5(1H,bs), 8.75(1H,bs)

Example 21(E)-N-[3-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(2-pyridyl)phenyl)-3-butenamide##STR99##

NMR(CDCl₃) δ; 1.5˜1.9(2H,m), 2.12(3H,s), 2.2˜2.9(6H,m), 3.08(2H,d,J=6.5Hz), 3.2˜3.6(2H,m), 3.82(6H,s), 6.34(1H,dt,J=15.8 Hz,6.5 Hz),6.50(1H,d,J=15.8 Hz), 6.6˜6.8(3H,m), 7.1˜7.4(2H,m), 7.46(2H,d,J=8.3 Hz),7.7˜7.8(2H,m), 7.96(2H,d,J=8.3 Hz), .870(1H,m)

Example 22(E)-N-[3-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(4-pyridyl)phenyl)-3-butenamide##STR100##

NMR(CDCl₃) δ; 1.6˜1.9(2H,m), 2.28(3H,s), 2.4˜2.8(6H,m), 3.14(2H,d,J=6.1Hz), 3.3˜3.6(2H,m), 3.88(3H,s), 3.90(3H,s), 6.48(1H,dt,J=16.6 Hz),6.60(1H,d,J=16.6 Hz), 6.6˜6.9(3H,m), 7.3˜7.7(7H,m), 8.71(2H,m)

Example 23(E)-N-[(3-((N'-(2-(3,4-Dimethoxyphenyl(ethyl)-N'-methyl)amino)propyl]-4-(4-(1H-pyrrol-1-yl)phenyl-3-butenamide##STR101##

NMR(CDCl₃) δ; 1.48˜1.92(2H,m), 2.19(3H,s), 2.35˜2.80(6H,m),3.05(2H,d,J=6.2 Hz), 3.20˜3.60(2H,m), 3.82(6H,s), 6.0˜6.5(4H,m),6.5˜6.8(3H,m), 6.9˜7.1(2H,m), 7.1˜7.4(4H,m)

Example 24(E)-N-[3-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-imidazo[1,2-a]pyridin-6-yl)phenyl)-3-butenamide##STR102##

NMR(CDCl₃) δ; 1.6˜1.9(2H,m), 2.23(3H,s), 2.7˜2.8(6H,m), 3.09(2H,d,J=6.1Hz), 3.3˜3.5(2H,m), 3.82(3H,s), 3.85(3H,s), 6.36(1H,dt,J=16.2 Hz,6.1Hz), 6.52(1H,d,J=1.62 Hz), 6.6˜6.9(3H,m), 7.2˜7.6(8H,m), 8.46(1H,m)

Example 25(E)-N-[3-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(1H-1,2,4-triazol-1-yl)phenyl)-3-butenamide##STR103##

NMR(CDCl₃) δ; 1.50˜1.85(2H,m), 2.20(3H,s), 2.18˜2.80(6H,m),3.02(2H,d,J=6.0 Hz), 3.2˜3.5(2H,m), 3.80((3H,s), 3.82(3H,s),6.22(1H,dt,J=6.0 Hz,16.2 Hz), 6.46(1H,d,J=16.2 Hz), 6.35˜6.78(3H,m),7.0˜7.3(1H,m), 7.3˜7.6(4H,m), 8.00(1H,s), 8.44(1H,s)

Example 26(E)-N-[3-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(1H-benzimidazol-1-yl)phenyl)-3-butenamide##STR104##

NMR(CDCl₃) δ; 1.44˜1.80(2H,m), 2.20(3H,s), 2.32˜2.80(6H,m),3.0(2H,d,J=6.0 Hz), 3.10˜3.44(2H,m), 3.72(3H,s), 3.76(3H,s),6.0˜6.44(2H,m), 6.48-6.76(3H,m), 7.10˜7.6(9H,m), 8.0(1H,s)

Example 27(E)-N-[3-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(1H-pyrazol-1-yl)phenyl)-3-butenamide ##STR105##

NMR(CDCl₃) δ; 1.4˜1.8(2H,m), 2.16(3H,s), 2.3˜2.7(6H,m), 3.0(2H,d,J=5.0Hz), 3.16˜3.40(2H,m), 3.76(6H,s), 5.96˜6.76(6H,m), 7.2˜7.7(7H,m),7.8(1H,d,J=3 Hz)

Example 28(E)-N-[3-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(1,3-oxazol-5-yl)phenyl)-3-butenamide##STR106##

NMR(CDCl₃) δ; 1.50˜1.86(2H,m), 2.18(3H,s), 2.30˜2.76(6H,m),3.05(2H,d,J=6.2 Hz), 3.20˜3.54(2H,m), 3.82(3H,s), 3.84(3H,s),6.22(1H,dt,J=15.1 Hz,6.2 Hz), 6.44(1H,d,J=15.1 Hz), 6.56˜6.76(3H,m),7.28(1H,s), 7.3˜7.66(5H,m), 7.86(1H,s)

Example 29(E)-N-[3-(N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(4(1H)-pyridon-1-yl)phenyl)-3-butenamide##STR107##

NMR(CDCl₃) δ; 1.5˜1.8(2H,m), 2.23(3H,s), 2.3˜2.8(6H,m), 3.05(2H,d,J=5.3Hz), 3.2˜3.5(2H,m), 3.82(3H,s), 3.84(3H,s), 6.0˜6.5(4H,m),6.5˜6.8(3H,m), 7.0˜7.6(7H,m)

Example 30(E)-N-[3-((N'-(2-(4-Methoxyphenyl)ethyl)-N'-allyl)amino)propyl]-4-(4-(1H-imidazol-1-yl)phenyl)-3-butenamide##STR108##

NMR(CDCl₃) δ; 1.50˜1.80(2H,m), 2.4˜2.7(6H,m), 3.04(2H,d,J=5.0 Hz),3.03(2H,d,J=7.2 Hz), 3.16˜3.44(2H,m), 3.7(3H,s), 4.96˜5.24(2H,m),5.5˜6.0(1H,m), 6.0˜7.5(13H,m), 7.76(1H,s)

Example 31(E)-N-[3-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)amino)propyl]-4-(4-(1H-imidazol-1-yl)phenyl)-3-butenamide##STR109##

NMR(CDCl₃) δ; 1.5˜1.9(2H,m), 2.32(1H,brs), 2.50˜3.00(6H,m),3.08(2H,d,J=7.0 Hz), 3.2˜3.5(2H,m), 3.84(3H,s), 3.86(3H,s),6.26(1H,dt,J=7.0 Hz, 14.4 Hz), 6.50(1H,d,J=14.4 Hz), 6.58˜6.80(3H,m),7.0˜7.55(7H,m), 7.78(1H,s)

Example 32(E)-N-[3-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-allyl)amino)propyl]-4-(4-(1H-imidazol-1-yl)phenyl)-3-butenamide##STR110##

NMR(CDCl₃) δ; 1.55˜1.80(2H,m), 2.30˜2.74(6H,m), 2.80˜3.25(4H,m),3.2˜3.5(2H,m), 3.74(6H,s), 4.98˜5.18(2H,m), 6.24(1H,dt,J=5.4 Hz,16.2Hz), 6.47(1H,d,J=16.2 Hz), 6.62˜7.45(10H,m), 7.78(1H,s)

Example 33N-[2-(3,4-Dimethoxyphenyl)ethyl]-N'-[(E)-4-(4-1H-imidazol-1-yl)phenyl)-3-butenoyl]homopiperazine##STR111##

NMR(CDCl₃) δ; 1.73˜2.07(2H,m), 2.41˜3.13(8H,m), 3.21˜3.83(6H,m),3.83(3H,s), 3.85(3H,s), 6.37˜6.57(2H,m), 6.61˜6.89(3H,m),7.14˜7.65(6H,m), 7.83(1H,s)

Example 34 (E)-N-[3-((N'-2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)-2-methylpropyl]-4-(4-(1H-imidazol-1-yl)phenyl)-3-butenamide##STR112##

NMR(CDCl₃) δ; 0.84(3H,d,J=7.0 Hz), 2.16(3H,s), 2.2˜2.8(7H,m),3.0(2H,d,J=6.0 Hz), 3.4˜3.8(2H,m), 3.8(6H,s), 5.96˜6.8(5H,m),7.0˜7.5(6H,m), 7.76(1H,s), 7.8˜8.1(1H,m)

Example 35(E)-N-[4-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butan-2-yl]-4-(4-(1H-imidazol-1-yl)phenyl)-3-butenamide##STR113##

NMR(CDCl₃) δ; 1.16(3H,d,J=7.0 Hz), 1.4˜1.8(2H,m), 2.2(3H,s),2.8-2.8(6H,m), 3.74(3H,s), 3.76(3H,s), 3.9˜4.2(1H,m), 6.0˜6.8(5H,m),7.04˜7.6(7H,m), 7.74(1H,s)

Example 36(E)-N-[4-((N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butan-2-yl]-4-(4-(1H-imidazol-1-yl)phenyl)-3-butenamide##STR114##

NMR(CDCl₃) δ; 1.18(3H,d,J=7.2 Hz), 1.4˜2.0(2H,m), 2.21(3H,s),2.3˜2.8(6H,m), 3.01(2H,d,J=6.6 Hz), 3.73(6H,s), 3.9˜4.3(1H,m),6.24(3H,s), 6.27(1H,dt,J=6.6 Hz,15.8 Hz), 6.44(1H,d,J=15.8 Hz),7.0˜7.5(7H,m), 7.76(1H,s)

EXAMPLES OF THE COMPOUND II Manufacturing Example 1(E)-4-(4-fluorophenyl)-3-butenoic acid ##STR115##

74.4 g of 4-fluorobenzaldehyde and 233.6 g of β-carboxyethyl-triphenylphosphonium chloride were suspended in 700 ml of tetrahydrofuran andthese were incubated on ice and stirred. Into this 500 mltetrahydrofuran solution of 141.4 g of potassium tert-butoxide was addedslowly dropwise. 30 minutes after temperature was brought to roomtemperature and then they were stirred for 10 hours. After addingthereto ice water and cleaning with ether, the hydrogen-ionconcentration of water layer was set to pH2 with undiluted hydrochloricacid. Extraction was then made with ethyl acetate. After drying withmagnesium sulfate and concentration made under reduced pressure, thesolid obtained was recrystallized from hydrous ethanol, and 53.98 g ofmarked compound (yield: 50%) was obtained as white needle crystal.

fusing point (°C.): 114 to 115

    ______________________________________                                        Value of elemental analysis: as C.sub.10 H.sub.9 FO.sub.2                                  C            H      F                                            ______________________________________                                        Theoretical value                                                                          66.64        5.04   10.55                                        Observed value                                                                             66.64        5.02   10.44                                        ______________________________________                                    

NMR(CDCl₃) δ; 3.28(2H,d,J=6.5 Hz), 6.16(1H,dt,J=6.5 Hz,16.2 Hz)6.50(1H,d,J=16.2 Hz), 7.2 to 7.5(4H,m), 9.36(1H,br)

In a same way as above, the following compound was obtained.

(E)-4-(2-fluorophenyl)-3-butenoic acid ##STR116##

Fusing Point (°C.): 61 to 62

    ______________________________________                                        Value of Elemental Analysis: as C.sub.10 H.sub.9 FO.sub.2                                        C      H                                                   ______________________________________                                        Theoretical Value  66.64  5.04                                                Observed Value     66.75  5.03                                                ______________________________________                                    

NMR(CDCl₃) δ; 3.30(2H,d,J=6.5 Hz), 6.17(1H,dt,J=6.5 Hz,16.6 Hz),6.68(1H,d,J=16.6 Hz), 6.9˜7.4(4H,m), 11.62(1H,br)

(E)-4-(3-fluorophenyl)-3-butenoic acid ##STR117##

Fusing Point (°C.): 66.5 to 67

    ______________________________________                                        Value of Elemental Analysis: as C.sub.10 H.sub.9 FO.sub.2                                   C          H      F                                             ______________________________________                                        Theoretical Value                                                                           66.64      5.04   10.55                                         Observed Value                                                                              66.66      4.95   10.51                                         ______________________________________                                    

NMR(CDCl₃) δ; 3.28(2H,d,J=6.5 Hz), 6.24(1H,dt,J=6.5 Hz,16.2 Hz),6.50(1H,d,J=16.2 Hz), 7.7˜8.4(4H,m), 11.92(1H,br)

(E)-4-(4-methylthio)phenyl)-3-butenoic acid ##STR118##

Fusing Point (°C.): 131 to 132

    ______________________________________                                        Value of Elemental Analysis: as C.sub.11 H.sub.12 O.sub.2 S                                  C      H        S                                              ______________________________________                                        Theoretical Value                                                                            63.43  5.81     15.40                                                                              (%)                                       Observed Value 63.78  5.78     15.34                                                                              (%)                                       ______________________________________                                    

NMR(CDCl₃) δ; 2.47(3H,s), 3.28(2H,d,J=6 Hz), 6.16(1H,dt,J=7 Hz,15 Hz),6.44(1H,d,J=15 Hz), 7.01˜7.35(4H,m)

(E)-4-(4-cyanophenyl-3-butenoic acid ##STR119##

Fusing Point (°C.): 111 to 113

    ______________________________________                                        Value of Elemental Analysis: as C.sub.11 H.sub.9 NO.sub.2                                    C           H      N                                           ______________________________________                                        Theoretical Value (%)                                                                        70.58       4.85   7.48                                        Observed Value (%)                                                                           70.61       4.96   7.41                                        ______________________________________                                    

NMR(CDCl₃) δ; 3.29(2H,d,J=5.7 Hz), 6.34(1H,dt,J=5.7 Hz,15.8 Hz),6.58(1H,d,J=15.8 Hz), 7.3˜7.7(4H,m), 9.84(1H,br)

(E)-4-(4-chlorophenyl-3-butenoic acid ##STR120##

Fusing Point (°C.): 118.5 to 110

    ______________________________________                                        Value of Elemental Analysis: as C.sub.10 H.sub.9 Cl.sub.2                                        C      H                                                   ______________________________________                                        Theoretical Value (%)                                                                            61.08  4.61                                                Observed Value (%) 61.12  4.67                                                ______________________________________                                    

    ______________________________________                                        Value of Elemental Analysis: as C.sub.11 H.sub.12 O.sub.3                                        C      H                                                   ______________________________________                                        Theoretical Value (%)                                                                            68.74  6.29                                                Observed Value (%) 68.92  6.23                                                ______________________________________                                         1483

    ______________________________________                                        Value of Elemental Analysis: As C.sub.11 H.sub.12 O.sub.3                                        C      H                                                   ______________________________________                                        Theoretical Value (%)                                                                            68.73  6.30                                                Observed Value (%) 68.84  6.20                                                ______________________________________                                    

NMR(CDCl₃) δ; 3.28(2H,d,J=6.0 Hz), 6.19(1H,dt,J=6.0 Hz,16.2 Hz),6.49(1H,d,J=16.2 Hz), 7.1˜7.4(4H,m), 11.32(1H,br)

(E)-4-(2-methoxyphenyl)-3-butenoic acid ##STR121##

NMR(CDCl₃) δ; 3.31(2H,dd,J=1.0 Hz,7.0 Hz), 3.86(3H,S) 6.27(1H,dt,J=7.0Hz,16.3 Hz), 6.7-7.5(5H,m) 10.5(1H,br)

(E)-4-(3-methoxyphenyl-3-butenoic acid ##STR122##

Fusing Point (°C.): 96.5-97.5

    ______________________________________                                        Value of Elemental Analysis: as C.sub.11 H.sub.12 O.sub.3                                        C      H                                                   ______________________________________                                        Theoretical Value (%)                                                                            68.74  6.29                                                Observed Value (%) 68.92  6.23                                                ______________________________________                                    

NMR(CDCl₃) δ; 3.29(2H,d,J=5.7 Hz), 3.80(3H,s), 6.28(1H,dt,J=5.7 Hz,15.8Hz), 6.45(2H,d,J=15.8 Hz), 6.7˜7.3(4H,m), 9.8(1H,bs)

(E)-4-(4-methoxyphenyl)-3-butenoic acid ##STR123##

Fusing Point (°C.): 102.5-104.5

    ______________________________________                                        Value of Elemental Analysis: As C.sub.11 H.sub.12 O.sub.3                                        C      H                                                   ______________________________________                                        Theoretical Value (%)                                                                            68.73  6.30                                                Observed Value (%) 68.84  6.20                                                ______________________________________                                    

NMR(CDCl₃) δ; 3.26(2H,d,J=6.8 Hz), 3.78(3H,s), 6.10(1H,dt,J=6.8 Hz,16.6Hz), 6.45(1H,d,J=16.6 Hz), 6.83(2H,d,J=8.6 Hz), 7.30(2H,d,J=8.6 Hz),11.26(1H,br)

(E)-4-(4-methylphenyl-3-butenoic acid ##STR124##

Fusing Point (°C.): 113-114

    ______________________________________                                        Value of Elemental Analysis: as C.sub.11 H.sub.12 O.sub.2                                       C    H                                                      ______________________________________                                        Theoretical Value (%)                                                                             74.97  6.87                                               Observed Value (%)  74.94  6.87                                               ______________________________________                                    

NMR(CDCl₃) δ; 2.32(3H,s), 3.27(2H,d,J=7.2 Hz), 6.18(1H,dt,J=7.2 Hz,16.2Hz), 6.49 (1H,d,J=16.2 Hz), 7.0˜7.4(4H,m), 11.0(1H,br)

(E)-4-(3,4-difluorophenyl)-3-butenoic acid ##STR125##

Fusing Point (°C.): 95-96

    ______________________________________                                        Value of Elemental Analysis: as C.sub.10 H.sub.8 F.sub.2 O.sub.2                                C    H                                                      ______________________________________                                        Theoretical Value (%)                                                                             60.61  4.07                                               Observed Value (%)  60.85  4.02                                               ______________________________________                                    

NMR(CDCl₃) δ; 3.28(2H,d,J=8 Hz) 6.10(1H,dt,J=8 Hz,16 Hz) 6.24(1H,d,J=16Hz) 6.9-7.3(3H,m)

(E)-4-(3,4-dimethoxyphenyl-3-butenoic acid ##STR126##

NMR(CDCl₃) δ;

3.24(2H,d,J=6.5 Hz), 3.82(3H,s), 3.84(3H,s), 6.06(1H,dt,J=6.5 Hz,16.2Hz), 6.40(1H,d,J=16.2 Hz), 6.8˜7.0(3H,m), 8.40(1H,br)

(E)-4-(3,4-methylenedioxyphenyl)-3-butenoic acid ##STR127##

Fusing Point (°C.): 114-115

    ______________________________________                                        Value of Elemental Analysis: As C.sub.11 H.sub.10 C.sub.4                                       C    H                                                      ______________________________________                                        Theoretical Value (%)                                                                             64.07  4.89                                               Observed Value (%)  64.28  4.95                                               ______________________________________                                    

NMR(CDCl₃) δ; 3.22(2H,d,J=8 Hz) 5.90(2H,S) 6.00(1H,dt,J=8 Hz,16 Hz)6.36(1H,d,J=16 Hz) 6.6-6.9(3H,m)

(E)-4-(3,4-methylenedioxy)phenyl-3-butenoic acid ##STR128##

Fusing Point (°C.): 114-115

    ______________________________________                                        Value of Elemental Analysis: as C.sub.11 H.sub.10 C.sub.4                                       C    H                                                      ______________________________________                                        Theoretical Value (%)                                                                             65.44  5.49                                               Observed Value (%)  65.56  5.61                                               ______________________________________                                    

NMR(CCDCl₃) δ; 3.20(2H,d,J=8 Hz) 4.18(4H,S) 6.00(1H,dt,J=8 Hz,16 Hz)6.32(1H,d,J=16 Hz) 6.6-6.9(3H,m)

(E)-4-(3,4-dichlorophenyl)-3-butenoic acid ##STR129##

Fusing Point (°C.): 77-78

    ______________________________________                                        Value of Elemental Analysis: As C.sub.10 H.sub.8 Cl.sub.2                                  C         H      Cl                                              ______________________________________                                        Theoretical Value (%)                                                                        51.98       3.49   30.68                                       Observed Value (%)                                                                           52.21       3.47   30.57                                       ______________________________________                                    

NMR(CCDCl₃) δ; 3.30(2H,d,J=6.5 Hz), 6.26(1H,dt,J=6.5 Hz,15.8 Hz),7.1˜7.5(3H,m), 9.8(1H,br)

(E)-4-(3,4,5-trimethoxyphenyl)-3-butenoic acid ##STR130##

Fusing Point (°C.): 85-87

    ______________________________________                                        Value of Elemental Analysis: as C.sub.13 H.sub.14 C.sub.5                                       C    H                                                      ______________________________________                                        Theoretical Value (%)                                                                             61.89  6.39                                               Observed Value (%)  61.90  6.33                                               ______________________________________                                    

NMR(CCDCR) δ; 3.26(2H,d,J=8 Hz) 3.80 (3H,S), 3.84 (6H,S) 6.08 (1H,dt,J=8Hz,16 Hz) 6.44 (1H,d,J=16 Hz) 6.56 (2H,S)

(E)-4-(4-dimethylamino)phenyl)-3-butenoic acid ##STR131##

Fusing Point (°C.): 203-204

    ______________________________________                                        Value of Elemental Analysis: As C.sub.12 H.sub.15 O.sub.2 N                                C         H      N                                               ______________________________________                                        Theoretical Value (%)                                                                        70.22       7.37   6.82                                        Observed Value (%)                                                                           70.36       7.21   6.73                                        ______________________________________                                    

NMR(CCDCl₃) δ; 2.94(6H,s), 3.25(2H,d,J=7 Hz), 6.00(1H,dt,J=7 Hz,16 Hz),6.40(1H,d,J=16 Hz), 6.55˜6.75(2H,m), 7.16˜7.35(2H,m)

(E)-4-(4-(acetylamino)phenyl)-3-butenoic acid ##STR132##

Fusing Point (°C.): 216-217

    ______________________________________                                        Value of Elemental Analysis: as C.sub.12 H.sub.13 C.sub.3 N                                C         H      N                                               ______________________________________                                        Theoretical Value (%)                                                                        65.74       5.98   6.39                                        Observed Value (%)                                                                           65.89       5.93   6.24                                        ______________________________________                                    

NMR(CDMSO) δ; 2.02(3H,s), 3.13(2H,d,J=6 Hz), 6.12(1H,dt,J=6 Hz,16 Hz),6.40(1H,d,J=16 Hz), 7.14˜7.60(4H,m)

(E)-4-(4-(methoxycarbony)phenyl)-3-butenoic acid ##STR133##

Fusing Point (°C.) 118.5-121

    ______________________________________                                        Value of Elemental Analysis: As C.sub.12 H.sub.12 O.sub.4                                       C    H                                                      ______________________________________                                        Theoretical Value (%)                                                                             65.44  5.49                                               Observed Value (%)  65.65  5.42                                               ______________________________________                                    

NMR(CCDCl₃) δ; 3.30(2H,d,J=6.1 Hz), 3.88(3H,s), 6.33(1H,dt,J=6.1 Hz,15.5Hz), 6.56(1H,d,J=15.5 Hz), 7.3˜7.5(2H,m), 7.8˜8.1(2H,m), 9.45(1H,br)

(E)-4-(4-carbamoyl)phenyl)-3-butenoic acid ##STR134##

Fusing Point (°C.): 247-249

    ______________________________________                                        Value of Elemental Analysis: As C.sub.11 H.sub.11 NO.sub.3                                 C         H      N                                               ______________________________________                                        Theoretical Value (%)                                                                        64.38       5.40   6.83                                        Observed Value (%)                                                                           64.54       5.38   6.78                                        ______________________________________                                    

NMR(CDMSO0d₆) δ; 3.20(2H,d,J=5.8 Hz), 6.34(1H,dt,J=5.8Hz,15.8 Hz),6.66(1H,d,J=15.8 Hz), 7.1˜7.6(3H,m), 7.6˜8.1(3H,m)

(E)-4-((2-isopropyloxy-4-methoxy-3-methyl)phenyl)-3butenoic acid##STR135##

Fusing Point (°C.): 116-117

    ______________________________________                                        Value of Elemental Analysis: As C.sub.15 H.sub.20 O.sub.4                                       C    H                                                      ______________________________________                                        Theoretical Value (%)                                                                             68.16  7.63                                               Observed Value (%)  68.22  7.68                                               ______________________________________                                    

NMR(CCDCl₃) δ; 1.26(6H,d,J=7 Hz), 2.12(3H,s), 3.26(2H,dd,J=1 Hz,6 Hz),3.80(3H,s), 4.10(1H,heptet,J=7 Hz), 6.06(1H,dt,J=6 Hz, 17 Hz),6.54(1H,d,J=9 Hz), 6.68(1H,d,J=17 Hz), 7.22(7.22(1H,d,J=9 Hz),8.40(1H,br)

Manufacturing Examples 2N-(2-(N'-methyl-N'-(2-(3,4-dimethoxyphenyl)ethyl)amino)ethyl)phthalimide##STR136##

8.08 g of hydroiodic acid ofN-methyl-(2-((3,4-dimethoxyphenyl)ethyl)amine, 8.46 g ofN-(4-bromobutyl)phthalimide, 8.29 g of potassium carbonate and 50 ml ofN,N'-dimethylformamide were mixed and the mixture was stirred at 80° C.for 4 hours. After completion of reaction the mixture was diluted withwater and extracted with chloroform. After drying with sulfuricanhydride of magnesium, it was filtered and the solvent was distilledout. The residue was purified by means of silica gel columnchromatography (solvent; chloroform:methanol=100:1) and 9.44 g of themarked compound (yield: 95%) was obtained as yellowish oily matter.

NMR(CCDCl₃) δ; 1.3˜1.9(4H,m), 2.2-2.9(9H,m) 3.65(2H,t,J=6.8 Hz),3.78(3H,S), 3.81(3H,S) 6.5˜6.9(3H,m), 7.5˜7.9(4H,m)

Manufacturing Examples 3N-methyl-N-(2-(3,4-dimethoxyphenyl)ethyl)-1,4-butandediamine ##STR137##

9.44 g ofN-(4-(N'-methyl-N'-(3,4-dimethoxyphenyl)ethyl)amino)butyl)phthalimide asobtained in the manufacturing example 2 and 1.27 ml of monohydrate ofhydrazine were dissolved into 50 ml of methanol and the solution wasrefluxed with heat for 2 hours. After cooling down to room temperature,the deposit was filtered and the methanol was distilled off. To this wasadded aqueous solution of caustic soda and extraction was made withchloroform; then dried up with potassium carbonate ahhydride. Thesolvent was distilled off and the residue was purified by means ofsilica gel column chromatography (solvent;chloroform:methanol:non-diluted aqueous ammonia=100:10:1) and 5.21 g ofthe marked compound (yield: 82%) was obtained as yellowish oily matter.

NMR(CCDCl₃) δ; 1.3˜1.8(4H,m), 2.2˜2.9(11H,m) 3.26(2H,bs), 3.84(3H,S)3.87(3H,S), 6.5˜6.9(3H,m)

The below shown compound was obtained in the same way as shown above.

N-methyl-N-(2-(3,4-dimethoxyphenyl)ethyl)-1,2-ethylenediamine (yellowoil), N-(3-aminopropyl)-3-(3,4-dimethoxyphenyl)pyrrolidine (yellow oil)and N-isopropyl-N-(2-phenylethyl)-1,3-propanediamine (yellow oil). Theyhave the following formulae, respectively. Results of NMR analysis areshown, respectively. ##STR138##

NMR(CCDCl₃) δ; 1.75(2H,bs), 2.1˜2.9(11H,m) 3.85(3H,S), 3.87(3H,S),6.5˜6.8(3H,m) ##STR139##

NMR(CCDCl₃ --CD₃ OD) δ; 1.5˜3.5(15H,m) 3.83(3H,S), 3.86(3H,S) 6.76(3H,S)##STR140##

NMR(CCDCl₃) δ; 0.98(3H,d,J=7 Hz) 1.04(3H,d,J=7 Hz) 1.5-1.8(2H,m)2.1-3.4(11H,m) 6.9-7.4(5H,m)

Manufacturing Example 4N-methyl-N-(2-(3,4-dimethoxyphenyl)ethyl)-N'-isopropyl-1,3-propanediamine##STR141##

3.87 g of N-methyl-N-(2-(3,4-dimethoxyphenyl)ethyl)-1,3-propanediamineand 15 ml of acetone were dissolved into 50 ml of ethanol. To this wasadded 0.1 g of platinum oxide and then hydrogenetion was made at roomtemperature and under pressure of 3 kg/cm². At the end of 3 hourscatalyst was concentrated after filtering and 4.52 of marked compoundwas obtained as yellow oily matter (yield: 100%).

NMR(CCDCl₃) δ; 1.06 (3H,d,J=7 Hz) 1.5-1.9 (2H,m) 2.2-2.9 (13H, m) 3.83(3H,5) 3.86 (3H,s) 6.6-6.9 (3H,m)

Manufacturing Examples 5(E)-N-(3-chloropropyl)-3-(4-fluorobenzilidene-2-pyrrolidinone ##STR142##

0.96 g of 60% sodium hydroxide, 2.58 ml of 1-chloro-3-iodopropane and 20ml of N,N-dimethylformamide were mixed and the mixture was stirred atroom temperature. To which 3.82 of(E)-3-(4-fluorobenzilidene)-2-pyrrolidinone dissolved into 20 ml ofN,N-dimethylformamide was added dropwise and stirred for 3 hours. Aftercompletion of reaction, the product was put into ice water and extractedwith ethyl acetate. After water washing, it was dried up with magnesiumof sulfuric anhydride and the solvent was distilled off. The residue waspurified by means of silica gel column chromatography (solvent;n-hexane:ethyl acetate=3:2) and 3.55 g of the marked compound (yield:66%) was obtained as white solid matter.

NMR(CCDCl₃) δ; 1.9˜2.3(2H,m), 2.9˜3.2(2H,m), 3.4˜3.7(6H,m),6.9˜7.6(5H,m)

By the same method as above, the following compound was obtained

(E)-N-(3-chloropropyl)-3-(3,4-(methylenedioxy)benzilidene-2-pyrrolidinone##STR143##

Yellowish solid matter

NMR(CCDCl₃) δ; 1.9˜2.3(2H,m), 2.9˜3.2(2H,m), 3.4˜3.7(6H,m), 5.99(2H,s),6.7˜7.1(3H,m), 7.1˜7.3(1H,m)

(E)-N-(3-chloropropyl-3-(4-cyanobenzilidene)-2-pyrrolidinone ##STR144##

NMR(CCDCl₃) δ; 1.9˜2.3(2H,m), 2.9˜3.2(2H,m), 3.4˜3.8(6H,m),7.2˜7.4(1H,m), 7.4˜7.8(4H, m)

Manufacturing Example 6(E)-N-(3-chloropropyl)-3-(4-fluorophenyl)propeneamide ##STR145##

Mixture of 4.15 g of 3-(4-fluorophenyl) propylenic acid, 2.37 ml ofthyonyl chloride and 20 ml of benzene was refluxed with heat for 3hours. After concentration under reduced pressure, a coarse acidchloride was obtained. It was then dissolved into 20 ml ofdichlormethane and the dissolved was added dropwise under incubation onice into a mixture of 4.23 g of 3-chloropropylamine hydrochloric acid,10.47 ml of N,N-diisopropylethylamine and 50 ml of dichlormethane. Atthe end of 1 hour, it was concentrated under reduced pressure. Afterdilution with water, extraction was effectuated with ethyl acetate. Thiswas washed with diluted hydrochloric acid and saturated aqueous sodiumbicarbonate, and then dried with magnesium of sulfuric anhydride. Thesolvent was distilled off and the residue was purified by silica gelcolumn chromatography (solvent; n-hexane:ethyl acetate=3:2) and 5.73 gof the marked compound (yield: 95%) was obtained as white solid.

NMR(CCDCl₃) δ; 1.9˜2.3(2H,m), 3.3˜3.7(4H,m), 6.20(1H,br),6.32(1H,d,J=15.8 Hz), 6.8˜7.1(2H,m), 7.2˜7.7(3H,m)

Working Example 1(E)-N-(3-(N'-(2-(2,3-dimethoxyphenyl)ethyl-N'-methyl)amino)propyl)-4-(4-fluorophenyl)-3-buteneamide##STR146##

A mixture of 30.0 g of (E)-4-(4-fluorophenyl)-3-butenoic acid, 14.6 mlof thyonyl chloride and 350 ml of benzene was refluxed with heat for 2hours. Concentration under reduced pressure gave a coarse acid chloride.It was dissolved into 200 ml of dichlormethane and the dissolved wasthen added dropwise, under incubation on ice, into a mixture of 47.1 gof N-methyl-N (2-(3,4-dimethoxyphenyl)ethyl-1,3-propanediamine, 26.3 ofpotassium carbonate anhydride and 400 ml of dichlormethane. After 30minutes the temperature was lowered down to room temperature and themixture was stirred for 30 minutes. After completion of reaction waterwas added, extraction was made with chloroform and drying applied withsulfuric anhydride of sodium. The solvent was distilled off and theresidue was purified by means of silica gel column chromatography(solvent; chloroform:methanol=25:1) and 55.3 g of the marked compound(yield: 79%) was obtained as yellow oily matter.

NMR(CCDCl₃) δ; 1.5˜1.8(2H,m), 2.18(3H,s), 2.3˜2.8(6H,m), 3.04(2H,d,J=6.8Hz), 3.2˜3.5(2H,m), 3.84(3H,s), 3.86(3H,s), 6.12(1H,dt,J=6.8 Hz,15.2Hz), 6.48(1H,d,J=15.2H), 7.6˜7.8(3H,m), 7.8˜8.1(2H,m), 8.1˜8.4(3H,m)

Working Example 2(E)-N-(3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl))-4-(4-fluorophenyl)-3-buteneamid-dihydrochloride##STR147##

55.3 g of(E)-N-(3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl))-4-(4-fluorophenyl)-3-buteneamideas obtained under the working example 1 was dissolved into 100 ml ofmethanol, to which was added methanolhydrogen chloride. Further etherwas added thererto to crystallize and 56.1 g of marked compound wasobtained (yield: 86% as slightly yellow powder.

Fusing Point (°C.): 101

    ______________________________________                                        Value of Elemental Analysis: as C.sub.24 H.sub.33 FCl.sub.2 N.sub.2           O.sub.3                                                                                   C    H        N      F                                            ______________________________________                                        Theoretical Value                                                                           59.13  6.82     5.75 3.89 (%)                                   Observed Value                                                                              59.13  6.83     5.60 3.91 (%)                                   ______________________________________                                    

WORKING EXAMPLE 3-69

The following compounds were produced by the same method as in theworking example 1 above.

Working Example 3 (E)-N-((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-methyl)amino)propyl))-3-phenylpropaneamide ##STR148##

Yellow oily matter

NMR(CCDCl₃) δ; 1.5˜1.9(2H,m), 2.31(3H,s), 2.4˜2.8(6H,m), 3.5˜3.6(2H,m),3.76(3H,s), 3.84(3H,s), 6.18(1H,d,J=16 Hz), 6.6˜6.8(3H,m),6.6˜6.8(3H,m), 7.0˜7.6(7H,m)

Working Example 4(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-3-(3,4-dimethoxyphenyl)propeneamide ##STR149##

Yellow oily matter

NMR(CCD₃ OD) δ; 1.6˜2.0(2H,m), 2.29(3H,s), 2.3˜2.8(6H,m), 3.2˜3.5(2H,m),3.76(3H,s), 3.78(3H,s), 3.81(6H,s), 6.44(1H,d,J=16 Hz), 6.7˜7.2(6H,m),7.50(1H,d,J=16 Hz)

Working Example 5(E)-N-((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl))-3-(2,6-dichlorophenylpropeneamide##STR150##

Yellow oily matter

NMR(CCDCl₃) δ; 1.6˜2.0(2H,m), 2.42(3H,s), 2.6˜2.9(6H,m), 3.3˜3.6(2H,m),3.80(3H,s), 3.84(3H,s), 6.40(1H,d,J=18 Hz), 6.6˜6.8(3H,m), 6.9˜7.8(5H,m)

Working Example 6(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-3-(2,5-dimethoxyphenyl)propeneamide##STR151##

Yellow oily matter

NMR(CCDCl₃) δ; 1.5˜1.9(2H,m), 2.30(3H,s), 2.4˜2.8(6H,m), 3.2˜3.5(2H,m),3.72(3H,s), 3.76(3H,s), 3.78(3H,s), 3.80(3H,s), 6.30(1H,d,J=18 Hz),6.6˜7.3(8H,m), 7.7(1H,d,J=18 Hz)

Working Example 7(E)-N-((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl))-3-(4-fluorophenyl)propeneamide##STR152##

Light yellowish oily matter

NMR(CCDCl₃) δ; 1.5˜1.9(2H,m), 2.28(3H,s), 2.3˜2.8(6H,m), 3.3˜3.6(2H,m),3.72(3H,s), 3.80(3H,s), 6.12(1H,d,J=18 Hz), 6.72(3H,s), 6.8˜7.6(6H,m)

Working Example 8(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-3-(3-fluorophenyl)propeneamide##STR153##

Yellow oily matter

NMR(CCDCl₃) δ; 1.6˜1.9(2H,m), 2.34(3H,s), 2.4˜2.9(6H,m), 3.3˜3.6(2H,m),3.72(3H,s), 3.81(3H,s), 6.09(1H,d,J=14 Hz), 6.6˜6.8(3H,m), 6.8˜7.6(6H,m)

Working Example 9(E)-N-((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl))-3-(4-cyanophenyl)propeneamide##STR154##

Light yellowish oily matter

NMR(CCDCl₃) δ; 1.6˜2.0(2H,m), 2.30(3H,s), 2.4˜3.0(6H,m), 3.3˜3.6(2H,m),3.72(3H,s), 3.84(3H,s), 6.14(1H,d,J=18 Hz), 6.72(3H,s), 7.2˜7.9(6H,m)

Working Example 10(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-3-(3-cyanophenyl)propeneamide##STR155##

Yellow oily matter

NMR(CCDCl₃) δ; 1.6˜1.9(2H,m), 2.30(3H,s), 2.4˜2.8(6H,m), 3.3˜3.6(2H,m),3.69(3H,s), 3.81(3H,s), 6.20(1H,d,J=15 Hz), 6.68(3H,s), 7.1˜7.7(6H,m)

Working Example 11(E)-N-((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl))-4-(3-cyanophenyl)-3-buteneamide##STR156##

Brown oily matter

NMR(CCDCl₃) δ; 1.5˜1.9(2H,m), 2.14(3H,s), 2.4˜2.8(6H,m), 3.02(2H,d,J=6.8Hz), 3.2˜3.5(2H,m), 3.84(3H,s), 3.86(3H,s), 6.1˜6.9(5H,m), 7.1˜7.7(5H,m)

Working Example 12(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-4-(2-cyanophenyl)-3-buteneamide##STR157##

Yellow oily matter

NMR(CCDCl₃) δ; 1.5˜1.9(2H,m), 2.13(3H,s), 2.4˜2.8(6H,m), 3.06(2H,d,J=6.8Hz), 3.2˜3.5(2H,m), 3.82(3H,s), 3.86(3H,s), 6.48(1H,dt,J=6.8 Hz,16.2Hz), 6.7˜6.9(4H,m), 7.1˜7.7(5H,m)

Working Example 13(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl))-3-(2-Trifluoromethyl)phenyl)propeneamide##STR158##

Yellow oily matter

NMR(CCDCl₃) δ; 1.6˜1.9(2H,m), 2.30(3H,s), 2.4˜2.8(6H,m), 3.3˜3.8(2H,m),3.71(3H,s), (3.79(3H,s), 6.10(1H,d,J=16 Hz), 6.6˜6.8(3H,m),7.2˜7.8(6H,m)

Working Example 14(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-3-(3-trifluoromethyl)phenyl)propeneamide##STR159##

Yellow oily matter

NMR(CCDCl₃) δ; 1.6˜2.0(2H,m), 2.32(3H,s), 2.4˜2.9(6H,m), 3.2˜3.7(2H,m),3.74(3H,s), 3.84(3H,s), 6.16(1H,d,J=18 Hz), 6.76(3H,s), 7.20(1H,br),7.4˜7.8(6H,m)

Working Example 15(E)-N-((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl))-3-(2-naphthyl)-propeneamide##STR160##

Yellow oily matter

NMR(CCDCl₃) δ; 1.7˜2.0(2H,m), 2.42(3H,s), 2.5˜2.9(6H,m), 3.4˜3.9(2H,m),3.71(3H,s), (3.76(3H,s), 6.30(1H,d,J=16 Hz), 6.76(3H,s), 7.2(1H,br),7.4˜8.0(8H,m)

Working Example 16(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-3(4chlorophenyl)propeneamide##STR161##

Yellow oily matter

NMR(CCDCl₃) δ; 1.6˜1.9(2H,m), 2.34(3H,s), 2.4˜2.9(6H,m), 3.3˜3.6(2H,m),3.76(3H,s), 3.84(3H,s), 6.10(1H,d,J=16 Hz), 6.7˜6.9(3H,m), 7.2(1H,br),7.3˜7.6(5H,m)

Working Example 17(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-3-(4-methanesulphonylphenyl)propeneamide##STR162##

Yellow oily matter

NMR(CCDCl₃) δ; 1.6˜2.0(2H,m), 2.36(3H,s), 2.4˜2.9(6H,m), 3.08(3H,s),3.3˜3.6(2H,m), 3.76(3H,s), 3.87(3H,s), 6.22(1H,d,J=16 Hz),6.7˜6.8(3H,m), 7.36(1H,br), 7.4˜7.7(3H,m), 7.8˜8.0(2H,m)

Working Example 18(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-3-(4-nitrophenyl)propeneamide##STR163##

Yellow oily matter 1.5˜2.0(2H,m), 2.32(3H,s), 2.4˜2.8 (6H,m),3.3˜3.6(2H,m), 3.71(3H,s), (3.82(3H,s), 6.10(1H,d,J=16 Hz), 6.6˜6.8(3H,m), 7.2˜7.6(4H,m), 8.0˜8.2(2H,m)

Working Example 19(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-3-(3,4-dichlorophenyl)propeneamide##STR164##

Slightly yellow oily water

NMR(CCDCl₃) δ; 1.6˜1.9(2H,m), 2.30(3H,s), 2.4˜2.8(6H,m), 3.3˜3.6(2H,m),3.72(3H,s), 3.82(3H,s), 6.02(1H,d,J=18 Hz), 6.70(3H,s), 7.1˜7.6(5H,m)

Working Example 20(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-4-(3,4-dichlorophenyl)-3-buteneamide##STR165##

Yellow oily matter

NMR(CCDCl₃) δ; 1.5˜1.8(2H,m), 2.20(3H,s), 2.4˜2.8(6H,m), 2.99(2H,d,J=7Hz), 3.2˜3.5(2H,m), 3.82(3H,s), 3.84(3H,s), 6.18(1H,dt,J=7 Hz,16 Hz),6.38(1H,d,J=16 Hz), 6.5˜6.9(3H,m), 7.0˜7.4(4H,m)

Working Example 21(E)-N-(((3-((N'-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-3-)4-(methylthio)phenyl)propeneamide##STR166##

White Crystal

NMR(CCDCl₃) δ; 1.5˜1.9(2H,m), 2.32(3H,s), 2.4˜2.9(9H,m), 3.2˜3.6(2H,m),3.75(3H,s), 3.82(3H,s), 6.08(1H,d,J=16 Hz), 6.6˜6.8(3H,m), 7.0˜7.7(6H,m)

Working Example 22(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-3-(3,4-methylenedioxyphenyl)propeneamide##STR167##

Yellow oily matter

NMR(CCDCl₃) δ; 1.5˜2.0(2H,m), 2.32(3H,s), 2.4˜2.8(6H,m), 3.2˜3.6(2H,m),3.76(3H,s), 3.84(3H,s), 5.94(2H,s), 5.96(1H,d,J=16 Hz), 6.6˜7.2(8H,m),7.40(1H,d,J=16 Hz

Working Example 23(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-3-(4-methoxyphenyl)propeneamide##STR168##

Yellow oily matter

NMR(CCDCl₃) δ; 1.6˜1.9(2H,m), 2.36(3H,s), 2.3˜2.8(6H,m), 3.3˜3.6(2H,m),3.76(3H,s), 3.80(3H,s), 3.82(3H,s), 6.06(1H,d,J=16 Hz), 6.6˜6.9(5H,m),7.02(1H,br), 7.2˜7.6(3H,m)

Working Example 24(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-3-(3-chlorophenyl)propeneamide##STR169##

Yellow oily matter

NMR(CCDCl₃) δ; 1.5˜2.0(2H,m), 2.32(3H,s), 2.4˜2.8(6H,m), 3.2˜3.6(2H,m)3.72(3H,s), 3.82(3H,s), 6.08(1H,d,J=16 Hz), 6.6˜6.8(3H,m), 7.1˜7.5(6H,m)

Working Example 25(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-3-(4-(methylphenyl)propeneamide##STR170##

Slightly yellowish oily matter

NMR(CCDCl₃) δ; 1.5˜1.9(2H,m), 2.30(3H,s), 2.32(3H,s), 2.4˜2.8(6H,m),3.3˜3.6(2H,m), 3.74(3H,s), 3.82(3H,s), 6.16(1H,d,J=17 Hz),6.6˜6.8(3H,m), 7.0˜7.4(5H,m), 7.50(1H,d,J=17 Hz)

Working Example 26(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-3-(3-fluoro-4-methyoxyphenyl)propeneamide ##STR171##

Slightly yellowish matter

NMR(CCDCl₃) δ; 1.5˜1.9(2H,m), 2.32(3H,s), 2.4˜2.8(6H,m), 3.3˜3.6(2H,m),3.78(3H,s), 3.86(3H,s), 3.92(3H,s), 6.00(1H,d,J=17 Hz), 6.7˜7.4(7H,m),7.46(1H,d,J=17 Hz)

Working Example 27(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-4-phenyl)-3-buteneamide##STR172##

Yellow oily matter

NMR(CCDCl₃) δ; 1.5˜1.9(2H,m), 2.30(3H,s), 2.4˜2.7(6H,m), 3.10(2H,d,J=8Hz), 3.2˜3.5(2H,m), 3.86(6H,s), 6.0˜6.5(2H,m), 6.5˜6.9(3H,m),7.0˜7.5(6H,m)

Working Example 28(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-3-(3,5-dimethoxyphenyl)propeneamide##STR173##

Slightly yellowish oily matter

NMR(CCDCl₃) δ; 1.5˜1.9(2H,m), 2.20(3H,m), 2.2˜2.7(6H,m), 3.2˜3.5(2H,m),3.66(9H,s), 3.72(3H,s), 6.16(1H,d,J=18 Hz), 6.2˜6.7(6H,m), 7.24(1H,br),7.36(1H,d,J=18 Hz)

Working Example 29(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-4-((2-isopropyloxy-4-methoxy-3-methyl)phenyl)-3-buteneamide##STR174##

Yellow oily matter

NMR(CDCl₃) δ; 1.28(6H,d,J=7 Hz), 1.5˜1.9(2H,m), 2.10(3H,s), 2.20(3H,s),2.3˜2.9(6H,m), 3.06(2H,d,J=6 Hz), 3.2˜3.5(2H,m), 3.76(3H,s), 3.82(3H,s),3.84(3H,s), 3.9˜4.3(1H,m), 6.04(,dt,J=6 Hz, 16 Hz), 6.4˜6.9(5H,m),7.04(1H,br), 8.23(1H,d,J=9 Hz)

Working Example 30(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-4-(2,4-difluorophenyl)-3-buteneamide##STR175##

Slightly yellowish oily matter

NMR(CDCl₃) δ; 1.5˜1.9(2H,m), 2.24(3H,s), 2.4˜2.8(6H,m), 3.04(2H,d,J=6Hz), 3.1˜3.5(2H,m), 3.90(6H,s), 6.0˜6.5(2H,m), 6.5˜7.0(5H,m),7.1˜7.4(2H,m)

Working Example 31(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-N-methyl-3-(3,4-dimethoxyphenyl)propeneamide ##STR176##

Slightly yellowish oily matter

NMR(CDCl₃) δ; 1.7˜2.0(2H,m), 2.2˜2.9(9H,m), 3.04, 3.16(total 3H,br s),3.84(6H,s), 3.90(6H,s), 6.6˜7.2(7H,m), 7.66(1H,d,J=16 Hz)

Working Example 32(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-N-ethyl-3-(4-dicyanophenyl)propeneamide ##STR177##

Yellowish oily matter

NMR(CDCl₃) δ; 1.0˜1.4(3H,m), 1.6˜2.0(2H,m), 2.30, 2.34(total 3H,s),2.4˜2.8(6H,m), 3.2˜3.6(4H,m), 3.84(6H,s), 6.6˜6.9(3H,m), 7.10(1H,d,J=18Hz), 7.5˜7.8(5H,m)

Working Example 33(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-N-ethyl-3-(4-chlorophenyl)propeneamide ##STR178##

Slightly yellowish oily matter

NMR(CDCl₃) δ; 1.0˜1.3(3H,m), 1.6˜2.0(2H,m), 2.3(3H,br), 2.3˜2.8(6H,m),3.2˜3.6(4H,m), 3.80(6H,s), 6.6˜6.8(3H,m), 6.90(1H,d,J=16 Hz),7.2˜7.6(4H,m), 7.62(1H,d,J=16 Hz)

Working Example 34(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-N-methyl-3-(4-fluorophenyl)propeneamide ##STR179##

Yellow oily matter

NMR(CDCl₃) δ; 1.6˜2.0(2H,m), 2.2˜2.8(9H,m), 3.00, 3.10(total 3H,s),3.3˜3.6(2H,m), 3.80(6H,s), 6.6˜6.8(3H,m), 6.8˜7.4(6H,m)

Working Example 35(E)-N-(((3-((N'-(2-(3.4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-N-methyl-4-(4-fluorophenyl)-3-buteneamide ##STR180##

Brown oily matter

NMR(CDCl₃) δ; 1.5˜2.0(2H,m), 2.28, 2.30(total 3H,s), 2.3˜2.8(6H,m),2.96(2H,d,J=8 Hz), 3.1˜3.6(5H,m), 3.84(6H,s), 6.0-6.6(2H,m),6.6˜7.4(7H,m)

Working Example 36(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-N-methyl-3-(3-fluorophenyl)propeneamide ##STR181##

Yellow oily matter

NMR(CDCl₃) δ; 1.5˜2.0(2H,m), 2.4˜2.9(9H,m), 3.00, 3.12(total 3H,s),3.3˜3.6(2H,m), 3.80(6H,s), 6.5˜6.8(3H,m), 6.8˜7.4(5H,m), 7.46(1H,d,J=14Hz)

Working Example 37(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)-amino)propyl)))-N-ethyl-3-(4-fluorophenyl)propeneamide ##STR182##

Yellow oily matter

NMR(CDCl₃) δ; 1.17, 1.24(total 3H,t,J=6 Hz), 1.6˜2.0(2H,m),2.2˜2.8(9H,m), 3.2˜3.6(2H,m), 3.80(6H,s), 6.7˜6.8(4H,m), 6.8˜7.1(2H,m),7.2˜7.7(3H,m)

Working Example 38(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-N-ethyl-4-(4-fluorophenyl)-3-buteneamide ##STR183##

Yellow oily matter

NMR(CDCl₃) δ; 1.10, 1.16(total 3H,t,J=6 Hz), 1.5˜1.9(2H,m),2.1˜2.8(9H,m), 3.1˜3.6(6H,m), 3.82(6H,s), 6.2˜6.4(2H,m), 6.6˜7.4(7H,m)

Working Example 39(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-N-cyclopentyl-4-(4-cyanophenyl)-3-buteneamide ##STR184##

Yellow oily matter

NMR(CDCl₃) δ; 1.3˜2.0(10H,m), 2.2˜2.8(9H,m), 2.9˜3.4(4H,m), 3.80(3H,s),3.82(3H,s), 3.9˜4.7(1H,br m), 6.2˜6.9(5H,m), 7.2˜7.6(4H,m)

Working Example 40(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-N-cyclopentyl-4-(4-methylphenyl)-3-buteneamide ##STR185##

Yellow oily matter

NMR(CDCl₃) δ; 1.3˜2.0(10H,m), 2.2˜2.9(9H,m), 3.0˜3.4(4H,m), 3.80(3H,s),3.82(3H,s) 3.9˜4.8(1H,br m), 6.20(1H,dt,J=6 Hz, 16Hz), 6.40(1H,d,J=16Hz), 6.5˜6.9(3H,m), 6.9˜7.3(4H,m)

Working Example 41(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-N-cyclopentyl-4-phenyl-3-buteneamide ##STR186##

Yellow oily matter

NMR(CDCl₃) δ; 1.2˜2.0(10H,m), 2.2˜2.9(9H,m), 3.0˜3.4(4H,m), 3.79(3H,s),3.81(3H,s), 3.9˜4.7(1H,br m), 6.20(1H,dt,J=6 Hz, 16 Hz), 6.44(1H,d,J=16Hz), 6.6˜6.8(3H,m), 7.1˜7.5(5H,m)

Working Example 42(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-N-cyclopentyl-4-(4-methoxyphenyl)-3-buteneamide ##STR187##

Yellow oily matter

NMR(CDCl₃) δ; 1.4˜2.0(10H,m), 2.1˜2.9(9H,m), 3.1˜3.4(4H,m), 3.76(3H,s),3.84(3H,s), 3.86(3H,s), 4.0˜4.8(1H,br m), 6.16(1H,dt,J=6 Hz, 16 Hz),6.41(1H,d,J=16 Hz), 6.6˜7.0(5H,m), 7.2˜7.4(2H,m)

Working Example 43(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-N-cyclopentylmethyl-4-(3,4-(methylenedioxy)-phenyl-3-buteneamide##STR188##

Yellow oily matter

NMR(CDCl₃) δ; 1.0˜1.9(11H,m), 2.0˜2.8(9H,m), 3.1˜3.5(6H,m), 3.80(3H,s),3.82(3H,s), 5.87(2H,s), 6.08(1H,dt,J=6 Hz, 16 Hz), 6.32(1H,d,J=16 Hz),6.5˜6.9(6H,m)

Working Example 44(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-N-aryl-4-(3,4-methylenedioxy)phenyl)-3-buteneamide ##STR189##

Yellow oily matter

NMR(CDCl₃) δ; 1.5˜2.0(2H,m), 2.2˜2.9(9H,m), 3.1˜3.5(4H,m),3.8˜4.1(8H,m), 5.0˜5.4(2H,m), 5.5˜5.9(1H,m), 5.97(2H,s), 6.1˜6.6(2H,m),6.6˜7.0(6H,m)

Working Example 45(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-N-propyl-4-(3,4-(methylenedioxy)-phenyl-3-buteneamide##STR190##

Yellow oily matter

NMR(CDCl₃) δ; 0.86, 0.90(total 3H,t,J=7 Hz), 1.3˜1.9(4H,m),2.1˜2.8(9H,m), 2.9˜3.5(6H,m), 3.08(3H,s), 3.82(3H,s), 5.86(2H,s),6.08(1H,dt,J=6 Hz, 16 Hz), 6.33(2H,d,J=16 Hz), 6.5˜6.9(6H,m)

Working Example 46(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)-amino)propyl)))-N-(2-methylpropyl)-4-(3,4-(methylenedioxy)phenyl)-3-buteneamide##STR191##

Yellow oily matter

NMR(CDCl₃) δ; 1.04(3H,d,J=7 Hz), 1.10(3H,d,J=7 Hz), 1.5˜2.1(3H,m),2.2˜2.8(9H,m), 2.9˜3.5(6H,m), 3.78(3H,s), 3.80(3H,s), 5.94(2H,s),6.08(1H,dt,J=6 Hz, 16 Hz), 6.31(2H,d,J=16 Hz), 6.5˜6.9(6H,m)

Working Example 47(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)-amino)propyl)))-N-(1-methylpropyl)-4-(3,4-(methylenedioxy)phenyl-3-buteneamide##STR192##

Yellow oily matter

NMR(CDCl₃) δ; 1.06, 1.08(total 3H,d,J=7 Hz), 1.08, 1.20(total 3H,d,J=7Hz), 1.3˜2.0(4H,m) 2.3˜2.9(9H,m), 3.0˜3.4(4H,m), 3.84(3H,s), 3.86(3H,s),5.98(2H,s), 6.28(1H,dt,J=6 Hz), 6.40(1H,d,J=16 Hz)

Working Example 48(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-N-cyclohexyl-4-(3,4-(methylenedioxy)phenyl)-3-buteneamide##STR193##

Yellow oily matter

NMR(CDCl₃) δ; 0.9˜2.1(12H,m), 2.2˜2.9(9h,m), 3.1˜3.4(4H,m), 3.84(3H,s),3.86(3H,s), 3.9˜4.4(1H,br), 5.92(2H,s), 6.1˜6.5(2H,m), 6.6˜7.0(6H,m)

Working Example 49(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-N-tert-butyl-4-(3,4-(methylenedioxy)phenyl-3-buteneamide##STR194##

Yellow oily matter

NMR(CDCl₃) δ; 1.44(9H,s), 1.5˜1.9(2H,m), 2.2˜2.9(9H,m), 3.1˜3.5(4H,m),3.81(3H,s), 3.83(3H,s), 5.87(2H,s), 6.08(1H,dt,J=6 Hz, 16 Hz),6.32(1H,d,J=16 Hz), 6.5˜6.9(6H,m)

Working Example 50(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-N-isopropyl-4-(3,4 ##STR195##

Yellow oily matter

NMR(CDCl₃) δ; 1.1˜2.0(10H,m), 2.2˜2.8(9H,m), 3.1˜3.4(4H,m), 3.86(3H,s),3.88(3H,s), 3.9˜4.8(1H,br m), 5.92(2H,s), 6.16(1H,dt,J=6 Hz, 16 Hz),6.41(1H,d,J=16 Hz), 6.8˜7.0(6H,m)

Working Example 51(E)-N-(((3-((N'-(2-(4-methoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-N-cyclopentyl-4-(3,4-(methylenedioxy)phenyl-3-buteneamide##STR196##

Yellow oily matter

NMR(CDCl₃) δ: 1.3˜2.0(10H,m), 2.3(3H,s), 2.3˜2.84(6H,m), 3.0˜3.32(4H,m),3.72(3H,s), 3.9˜4.5(1H,m), 5.86(2H,s), 6.1(1H,dt,J=6 Hz, 16 Hz),6.3(1H,d,J=16 Hz); 6.6˜7.16(7H,m).

Working Example 52(E)-N-(((3-((N'-(2-(4-dimethoxyphenyl)ethyl)-N'-methyl)-amino)propyl)))-N-cyclopentyl-4-(3,4-(methylenedioxy)phenyl)-3-buteneamide##STR197##

Yellow oily matter

NMR(CDCl₃) δ: 1.3˜2.0(10H,m), 2.26(3H,s), 2.3˜2.9(6H,m), 3.6˜3.5(4H,m),3.72(3H,s), 3.92˜4.56(1H,m), 5.86(2H,s), 6.08(1H,dt,J=6 Hz, 16 Hz),6.32(1H,d,J=16 Hz), 6.5˜7.24(7H,m),

Working Examples 53(E)-N-(((3-((N'-(2-(4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-2-cyano-3-(3,4-(dimethoxyphenyl)propeneamide ##STR198##

Yellow oily matter

NMR(CDCl₃) δ; 1.6˜1.9(2H,m), 2.36(3H,s), 2.5˜2.9(6H,m), 3.3˜3.6(2H,m),3.76(3H,s) 3.82(3H,s), 3.90(6H,s), 6.68(3H,s), 6.82(1H,d,J=8 Hz),7.40(1H,dd,J=3 Hz, 8 Hz), 7.64(1H,d,J=3 Hz), 8.12(1H,s), 8.76(1H,

Working Example 54(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-3-methyl-3-(3,4-(dimethoxyphenyl)propeneamide ##STR199##

Yellow oily matter

NMR(CDCl₃) δ; 1.6˜2.0(2H,m), 2.02(3H,d,J=2 Hz), 2.36(3H,s),2.4˜2.9(6H,m), 3.3˜3.6(2H,m), 3.78(3H,s), 3.80(3H,s), 3.82(3H,s),3.86(3H,s), 6.5˜6.8(3H,m), 6.8˜7.0(3H,m), 7.08(1H,d,J=2 Hz), 7.60(1H,br)

Working Example 55(E)-N-(((S-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-2-fluoro-3-phenyl)propeneamide ##STR200##

Yellow oily matter

NMR(CDCl₃) δ; 1.6˜2.0(2H,m), 2.32(3H,s), 2.4˜2.9(6H,m), 3.3˜3.7(2H,m),3.78(3H,s), 3.82(3H,s), 6.6˜6.8(3H,m), 7.0˜7.7(6H,m), 8.3(1H,br)

Working Example 56(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)aminopropyl)))-2-methyl-3-(4-fluorophenyl)propeneamide ##STR201##

Yellow oily matter

NMR(CDCl₃) δ; 1.6˜1.9(2H,m), 1.96(3H,d,J=3 Hz), 2.32(3H,s),2.4˜2.8(6H,m), 3.3˜3.6(2H,m), 3.88(3H,s), 3.91(3H,s), 6.5˜6.8(3H,m),6.8˜7.4(5H,m), 7.70(1H,br)

Working Example 57(E)-N-(((S-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-2-cyano-3-phenylpropeneamide ##STR202##

Yellow oily matter

NMR(CDCl₃) δ; 1.6˜1.9(2H,m), 2.3˜2.9(9H,m), 3.3˜3.6(2H,m), 3.78(3H,s),3.84(3H,s), 6.74(3H,s), 7.4˜7.6(2H,m), 7.8˜8.0(3H,m), 8.28(1H,s),8.90(1H,br)

Working Example 58(E)-N-(((3-((N'-(2-(4-methoxyphenyl)ethyl)-N'-aryl)amino)propyl)))-4-(4-fluorophenyl)-3-buteneamide ##STR203##

Yellow oily matter

NMR(CDCl₃) δ; 1.4˜1.8(2H,m), 2.5˜2.7(6H,m), 2.9˜3.2(4H,m),3.2˜3.5(2H,m), 3.76(3H,s), 5.0˜5.3(2H,m), 5.5˜6.6(3H,m), 6.7˜7.4(9H,m)

Working Example 59(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-isopropyl)amino)propyl)))-3-(4-fluorophenylpropeneamide ##STR204##

Yellow oily matter

NMR(CDCl₃) δ; 1.01(6H,d,J=7 Hz, 1.5˜1.9(2H,m), 2.3˜2.9(6H,m ),2.9˜3.3(1H,m), 3.3˜3.6(2H,m), 3.75(3H,s), 3.85(3H,s), 6.04(1H,d,J=16Hz), 6.5˜6.8(3H,m), 6.8˜7.7(6H,m)

Working Example 60(E)-N-(((3-((N'-(2-phenylethyl)-N'-methyl)amino)propyl)))-3-(4-fluorophenyl)propeneamide##STR205##

White crystal

NMR(CDCl₃) δ; 1.5˜1.9(2H,m), 2.30(3H,s), 2.4˜2.9(6H,m), 3.3˜3.6(2H,m),5.99(1H,d,J=16 Hz), 6.8˜7.6(11H,m)

Working Example 61(E)-N-(((3-((N'-(2-phenylethyl)-N'-isopropyl)amino)propyl))-3-(4-fluorophenyl)propeneamide##STR206##

Yellow oily matter

NMR(CDCl₃) δ; 0.99(6H,d,J=7 Hz), 1.5˜1.9(2H,m), 2.5˜2.8(6H,m),2.9˜3.3(1H,m), 3.3˜3.6(2H,m), 5.99(1H,d,J=16 Hz), 6.9˜7.6(11H,m)

Working Example 62(E)-N-(((3-((N'-(2-(3-methoxyphenyl)ethyl)-N'-isopropyl)amino)propyl)))-3-(4-fluorophenyl)propeneamide ##STR207##

Yellow oily matter

NMR(CDCl₃) δ; 1.02(6H,d,J=7 Hz), 1.5˜1.9(2H,m), 2.5˜2.9(6H,m),2.9˜3.1(1H,m), 3.3˜3.6(2H,m), 3.75(3H,s), 6.00(1H,d,J=16 Hz),6.6˜7.7(10H,m)

Working Example 63(E)-N-(((3-((N'-(2-(2,5-dimethoxyphenyl)ethyl)-N'-methyl)-amino)propyl)))-4-(4-fluorophenyl)-3-buteneamide ##STR208##

Yellow oily matter

NMR(CDCl₃) δ; 1.5˜1.8(2H,m), 2.16(3H,s), 2.3˜2.8(6H,m), 3.00(2H,d,J=8Hz), 3.2˜3.5(2H,m), 3.74(6H,s), 5.9˜6.6(2H,m), 6.0˜7.6(8H,m)

Working Example 64(E)-N-(((3-((N'-(2-(3,4-ethylenedioxy)phenyl)ethyl)-N'-methyl)amino)propyl)))-4-(4-fluorophenyl)-3-buteneamide ##STR209##

Slightly brownish oily matter

NMR(CDCl₃) δ; 1.5˜1.8(2H,m), 2.10(3H,s), 2.3˜2.6(6H,m), 2.96(2H,d,J=6Hz), 3.1˜3.4(2H,m), 4.14(4H,s), 5.8˜7.4(10H,m)

Working Example 65(E)-N-(((3-(4-(3,4-dimethoxyphenyl)piperidine-1-yl)propyl)))-4-(4-fluorophenyl)-3-buteneamide##STR210##

Light yellow solid

NMR(CDCl₃) δ; 1.6˜2.6(11H,m), 2.9˜3.2(2H,m), 3.2˜3.5(2H,m), 3.81(6H,s),6.15(1H,dt,J=7 Hz, 16 Hz), 6.44(1H,d,J=16 Hz), 6.6˜7.4

Working Example 66 (E)-N-(((3-((N'-(2-(4-pridyl)ethyl)-N'-methyl)amino)propyl)))-4-(4-fluorophenyl)-3-buteneamide ##STR211##

Yellow oily matter

NMR(CDCl₃) δ; 1.4˜1.8(2H,m), 2.15(3H,s), 2.3˜2.7(6H,m), 3.00(2H,d,J=7Hz), 3.1˜3.5(2H,m), 6.04(1H,dt,J=7 Hz, 16 Hz), 6.36(1H,d,J=16 Hz),6.7˜7.3(7H,m), 8.3˜8.5(2H,m)

Working Example 67(E)-N-(1-(2-(3,4-dimethoxyphenyl)ethyl)piperidine-4-yl)-3-(fluorophenyl)propeneamide ##STR212##

White solid

NMR(CDCl₃) δ; 1.3˜1.8(2H,m), 1.9˜2.4(6H,m), 2.4˜3.1(7H,m), 3.86(3H,s),3.88(3H,s), 5.68(1H,d,J=8 Hz), 6.32(1H,d,J=16 Hz), 6.6˜6.9(3H,m),6.9˜72. (2H,m), 7.3˜7.7(3H,m)

Working Examples 68(E)-N-(((4-((N'-(2-(3,4-dimethoxyphenyl)ethyl-N'-methyl)amino)piperidine 1-yl)-3-(4-fluorophenyl)-3-propeneamide ##STR213##

Light Yellow oily matter

NMR(CDCl₃) δ; 1.2˜2.1(4H,m), 2.36(3H,s), 2.5˜3.2(7H,m), 3.87(3H,s),3.89(3H,s), 6.6˜6.8(3H,m), 6.9˜7.3(4H,m), 7.4˜7.8(3H,m)

Working Example 69(E)-N-(((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)-ethyl-4-(4-fluorophenyl)-3-buteneamide##STR214##

Yellow oily matter

NMR(CDCl₃) δ; 2.28(3H,s), 2.4˜2.8(6H,m), 3.00(2H, d, J=7 Hz),3.1˜3.4(2H,m), 3.83(6H,s), 6.12(1H,br), 6.14(1H,dt,J=7 Hz, 16 Hz),6.48(1H,d,J=16 Hz), 6.6˜6.8(3H,m), 6.8˜7.1(2H,m), 7.2˜7.4(2H,m)6.35(1H,br), 6.49(1H,d,J=16 Hz), 6.6˜6.8(3H,m), 6.8˜7.1(2H,m),7.2˜7.4(2H,m)

Working Example 70(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl-N'-methyl)amino)propyl-4-(4-cyanophenyl)-3-buteneamide ##STR215##

A mixture of 0.72 g of (E)-4-(4-cyanophenyl)-3-butenoic acid, 1.07 g ofN-methyl-N-(2-(3,4-dimethoxyphenyl)ethyl)-1,3-propanediamine, 0.87 g ofN,N'-dicyclohexylcarbodiimide, 0.57 g of N-hydroxybenzotriazole and 13ml of acetnitrile was stirred at 70° C. for 30 minutes.

It was then incubated to reduce the temperature. The the depositi wasfiltered and concentrated.

To this was added water solution of potassium carbonate and extractionwas performed with chloroform and then drying was applied with sodiumsulfuric anhydride. The solvent was concentrated and the residue waspurified by means of silica gel column chromatography (solvent;dichloromethane: methanol=20 : 1) and the marked compound 1.52 g(yield:93%) was obtained as yellow oily matter.

NMR(CDCl₃) δ; 1.5˜1.8(2H,m), 2.14(3H,s), 2.4-2.8(6H,m), 3.01(2H,d,J=7Hz), 3.2˜3.5(2H,m), 3,84(3H,s), 3.86(3H,s), 6.1˜6.5(2H,m),6.6˜6.8(3H,m), 7.1˜7.0

WORKING EXAMPLE 71-95

The following compounds were produced by the same method as above.

Working Example 71(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl-N'-methyl)amino)propyl)))-4-(2-fluorophenyl)-3-buteneamide ##STR216##

Yellow oily matter

NMR(CDCl₃) δ; 1.5˜1.8(2H,m), 2.17(3H,s), 2.3˜2.7(6H,m), 3.06(2H,d,J=7Hz), 3.2˜3.5(2H,m), 3.82(3H,s), 3.84(3H,s), 6.32(1H,dt,J=7 Hz, 16 Hz),6.5˜6.8(4H,m), 6.9˜7.2(3H,m), 7.2˜7.5(2H,m)

Working Example 72(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-4-(3-fluorophenyl)-3-buteneamide ##STR217##

Yellow oily matter

NMR(CDCl₃) δ; 1.5˜1.8(2H,m), 2.18(3H,s), 2.3˜2.7(6H,m), 3.02(2H,d,J=7Hz), 3.2˜3.5(2H,m), 3.82(3H,s), 3.84(3H,s), 6.20(1H,dt,J=7 Hz, 16 Hz),6.43(1H,d,J=16 Hz), 6.6˜7.4(8H,m)

Working Example 73(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-4-(4-(dimethylamino)phenyl)-3-buteneamide ##STR218##

Yellow oily matter

NMR(CDCl₃) δ; 1.4˜1.8(2H,m), 2.16(3H,s), 2.2˜2.8(6H,m), 2.93(6H,s),3.03(2H,d,J=7 Hz), 3.1˜3.5(2H,m), 3.84(3H,s), 3.85(3H,s), 5.98(1H,dt,J=7Hz, 16 Hz), 6.32(1H,d,J=16 Hz), 6.4˜6.8(5H,m), 7.0˜7.3(3H,m)

Working Example 74(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-4-(3,4,5-trimethoxyphenyl)-3-buteneamide ##STR219##

Yellow oily matter

NMR(CDCl₃) δ; 1.6˜1.9(2H,m), 2.28(3H,s), 2.4˜2.8(6H,m), 3.04(2H,d,J=6Hz), 3.2˜3.5(2H,m), 3.80(9H,s), 3.82(3H,s), 3.84(3H,s), 610(1H,dt,J=6Hz, 16 Hz), 6.44(1H,d,J=16 Hz), 6.5˜6.8(6H,m)

Working Example 78(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-4-(4-methoxyphenyl)-3-buteneamide ##STR220##

Yellow oily matter

NMR(CDCl₃) δ; 1.5˜1.8(2H,m), 2.18(2H,s), 2.3˜2.7(6H,m), 3.03(2H,d,J=7Hz), 3.2˜3.5(2H,m), 3.76(3H,s), 3.82(3H,s), 3.86(3H,s), 6.06(1H,dt,J=7Hz, 16 Hz), 6.42(1H,d,J=16 Hz), 6.6˜6.9(5H,m), 7.2˜7.4(3H,m)

Working Example 76(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-4-(3-methoxyphenyl)-3-buteneamide ##STR221##

Yellow oily matter

NMR(CDCl₃) δ; 1.5˜1.9(2H,m), 2.20(3H,s), 2.3˜2.8(6H,m), 3.04(2H,d,J=6.2Hz), 3.1˜3.5(2H,m), 3.75(3H,s), 3.83(3H,s), 3.85(3H,s), 6.25(1T, dt,J=6.2 Hz, 15.8 Hz), 6.40(1H,d,J=15.8 Hz), 6.5˜7.4(8H,m)

Working Example 77(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)-amino)propyl)))-4-(2-methoxyphenyl)-3-buteneamide ##STR222##

Yellow oily matter

NMR(CDCl₃); 1.5˜1.8(2, m) 2.20(3H,s) 2.2˜2.7(6H,m) 3.09(2H,dd,J=(1.0,7.0 Hz) 3.2˜3.5(2H,m), 3.76(3H,s) 3.84(6H,s), 6.2(1H,dt,J=7.01 and 16.0Hz) 6.5˜7.0 (6H,m) 7.1˜7.5(3H,m)

Working Example 78(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-3-(4-(acetylamino)phenyl)propeneamide ##STR223##

Yellow amorphous matter

NMR(CDCl₃) δ; 1.5˜1.9(2H,m), 2.16(3H,s), 2.32(3H,s), 2.4˜2.9(6H,m),3.3˜3.6(2H,m), 3.74 (3H,s), 3.82(3H,s), 6.10(1H,d,J=16 Hz),6.6˜6.8(3H,m), 7.1˜7.8(7H,m)

Working Example 79(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-4-(4-(acetylamino)phenyl)-3-buteneamide ##STR224##

Yellow oily matter

NMR(CDCl₃) δ; 1.6˜1.9(2H,m), 2.14(3H,s), 2.18(3H,s), 2.3˜2.8(6H,m),2.96(2H,d,J=7 Hz), 3.1˜3.4(2H,m), 3.81(3H,s), 3.84(3H,s), 6.01(1H,dt,J=7Hz, 15 Hz), 6.33(1H,d,J=15 Hz), 6.4˜6.8(3H,m), 6.9˜7.6(7H,m), 8.82(1H,s)

Working Example 80(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-4-(4-(chlorophenyl)-3-buteneamide ##STR225##

Yellow oily matter

NMR(CDCl₃) δ; 1.5˜1.8(2H,m), 2.18(3H,s), 2.4˜2.8(6H,m), 3.02(2H,d,J=7Hz), 3.2˜3.5(2H,m), 3.82(3H,s), 3.86(3H,s), 6.16 (1H,dt,J=7Hz, 16 Hz),6.43(1H,d,J=16 Hz), 6.6˜6.9(3H,m), 7.1˜7.4(5H,m)

Working Example 81(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-4-(4-(methanesulfonyl)phenyl)-3-buteneamide ##STR226##

Yellow oily matter

NMR(CDCl₃) δ; 1.4˜1.9(2H,m), 2.2(3H,s), 2.3˜2.8(6H,m), 3.00(3H,s),3.02(2H,d,J=4 Hz), 3.1˜3.5(2H,m), 3.81(3H,s), 3.84(3H,s), 6.3˜6.9(5H,m),7.0˜7.9(5H,m)

Working Example 82(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-4-(4-(methylthio)phenyl)-3-buteneamide ##STR227##

Yellow oily matter

NMR(CDCl₃) δ; 1.4˜1.8(2H,m), 2.17(3H,s), 2.3˜2.8(9H,m), 3.03(2H,d,J=7Hz), 3.1˜3.4(2H,m), 3.84(3H,s), 3.85(3H,s), 5.9˜6.8(5H,m), 6.9˜7.4(5H,m)

Working Example 83(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-4-(4-(methyl)phenyl)-3-buteneamide ##STR228##

Yellow oily matter

NMR(CDCl₃) δ; 1.5˜1.8(2H,m), 2.17(3H,s), 2.31(3H,s), 2.4˜2.8(6H,m),3.03(2H,d,J=7 Hz), 3.2˜3.5(2H,m), 3.83(3H,s)

Working Example 84(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-4-(4-(methoxycarbonyl)phenyl)-3-buteneamide ##STR229##

Yellow oily matter

NMR(CDCl₃) δ; 1.5˜1.4(2H,m), 2.18(3H,s) 2.3˜2.7(6H,m), 3.02(2H,d,J=6 Hz)3.2˜3.5(2H,m), 3.82(3H,s), 3.84(3H,s) 3.88(3H,s), 6.26(1H,dt,J=6 Hz, 16Hz) 6.46(1H,d,J=16 Hz) 6.5˜6.8(3H,m) 7.1˜7.5(3H,m), 7.8˜8.0(2H,m)

Working Example 85 (E)-N-(((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-4-(3,4-(ethylenedioxy)phenyl)-3-buteneamide ##STR230##

Slightly yellowish oily matter

NMR(CDCl₃) δ; 1.5˜1.8(2H,m), 2.16(3H,s), 2.4˜2.7(2H,m), 3.02(2H,d,J=6Hz), 3.2˜3.5(2H,m), 3.92(3H,s), 3.94(3H,s), 4.18 (4H,s), 5.8˜6.5(2H,m),6.6˜6.9(6H,m), 7.15(1H,br)

Working Example 86(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-4-(3,4-(difluoro)phenyl)-3-buteneamide ##STR231##

Slightly yellowish oily matter

NMR(CDCl₃) δ; 1.5˜1.8(2H,m), 2.22(3H,s), 2.3˜2.8(6H,m), 3.00(2H,d,J=6Hz), 3.1˜3.3(2H,m), 3.84(3H,s), 3.88(3H,s), 6.10 (1H,dt,J=6 Hz, 16 Hz),6.26(1H,d,J=16 Hz), 6.3˜6.8(2H,m), 6.8˜7.3(4H,m)

Working Example 87(E)-N-(((3-((N'-(2-(3,4-(methylenedioxy)phenyl)ethyl)-N'-methyl)amino)propyl)))-4-(4-(fluorophenyl)-3-buteneamide ##STR232##

Slightly yellowish oily matter

NMR(CDCl₃) δ; 1.5˜1.8(2H,m), 2.12(3H,s), 2.1˜2.6(6H,m), 2.96(2H,d,J=8Hz), 3.1˜3.4(2H,m), 5.84(2H,s), 5.9˜7.4(10H,m)

Working Example 88(E)-N-(((3-((N'-(2-(3,4,5-trimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-4-(4-fluorophenyl)-3-buteneamide ##STR233##

Yellowish brown oily matter

NMR(CDCl₃) δ; 1.5˜1.8(2H,m), 2.18(3H,s), 2.3˜2.7(6H,m), 3.04(2H,d,J=8Hz), 3.2˜3.5(2H,m), 3.92(9H,s), 5.9˜6.5(4H,m), 6.8˜7.4(5H,m)

Working Example 89(E)-N-(((3-((N'-(2-(4-(methoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-4-(4-fluorophenyl)-3-buteneamide ##STR234##

Slightly yellowish oily matter

NMR(CDCl₃) δ; 1.4˜1.8(2H,m), 2.12(3H,s), 2.2˜2.7(6H,m), 2.96(2H,d,J=8Hz), 3.1˜3.5(2H,m), 3.70(3H,s), 5.8˜6.5(2H,m), 6.6˜7.4(9H,m)

Working Example 90(E)-N-(((3-((N'-(2-(3,4-methylenedioxy)phenyl)ethyl)-N'-methyl)amino)propyl)))-4-(3,4-methylenedioxy)phenyl)-3-buteneamide##STR235##

Slightly yellowish solid matter

NMR(CDCl₃) δ; 1.4˜1.8(2H,m), 2.16(3H,s), 2.4˜2.6(6H,m), 3.00(2H,d,J=8Hz), 3.2˜3.5(2H,m), 5.90(2H,s), 5.92(2H,s), 6.0˜7.0(8H,m), 7.15(1H,br)

Working Example 91(E)-N-(((3-((N'-(2-(4-fluorophenyl)ethyl)-N'-methyl)amino)-propyl)))-4-(3,4-methylenedioxy)phenyl)-3-buteneamide##STR236##

Slightly yellowish solid matter

NMR(CDCl₃) δ; 1.5˜1.8(2H,m), 2.16(3H,s), 2.3˜2.7(6H,m), 3.02(2H,d,J=8Hz), 3.2˜3.5(2H,m), 5.90(2H,s), 6.0˜6.6(2H,m), 6.6˜7.3(8H,m)

Working Example 92(E)-N-(((3-((N'-(2-(4-methoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-4-(3,4-methylenedioxy)phenyl)-3-buteneamide##STR237##

Slightly yellowish solid matter

NMR(CDCl₃) δ; 1.5˜1.8(2H,m), 2.18(3H,s), 2.3˜2.8(6H,m), 3.00(2H,d,J=8Hz), 3.2˜3.5(2H,m), 3.76(3H,s), 5.90(2H,s), 5.8˜6.5(2H,m), 6.8˜7.3(8H,m)

Working Example 93(E)-N-(((3-((N'-(2-(4-methoxyphenyl)ethyl)-N'-aryl)amino)propyl)))-4-(3,4-methylenedioxy)phenyl)-3-buteneamide##STR238##

Slightly brownish oily matter

NMR(CDCl₃) δ; 1.4˜1.8(b 2H,m), 2.4˜2.7(6H,m), 2.9˜3.2(4H,m),3.1˜3.5(2H,m), 3.76(3H,s), 5.0˜5.3(2H,m), 5.6˜6.5(5H,m), 6.6˜7.1(8H,m)

Working Example 94(E)-N-(((3-((N'-(2-(3-methoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-4-(3,4-methylenedioxy)phenyl-3-buteneamide##STR239##

Slightly brownish oily matter

NMR(CDCl₃) δ; 1.4˜1.8(2H,m), 2.14(3H,s), 2.3˜2.7(6H,m), 2.94(2H,d,J=8Hz, 3.1˜3.5(2H,m), 3.72(3H,s), 5.7˜6.4(4H,m), 6.5˜7.2(8H,m)

Working Example 95N-(((2-(3,4-dimethoxyphenyl)ethyl-N'-((((E)-4-(3,4-methylenedioxy)phenyl)-3-butenoly))))homopiperazine##STR240##

Yellow oily matter

NMR(CDCl₃) δ; 1.73˜2.08(2H,m), 2.49˜3.05(8H,m) 3.26(2H,d,J=7 Hz),3.35˜3.78(4H,m) 3.85(3H,s), 3.87(3H,s), 5.93(2H,f) 6.16(1H,dt;J=15 Hz, 7Hz) 1.42(1H,d,J=15 Hz) 6.57˜6.90(6H,m)

Working Example 96(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-4-(3,4-methylenedioxy)phenyl)-3-buteneamide##STR241##

A mixture composed of 37.45 g of(E)-4-(3,4-(methylenedioxy)phenyl)-3-butenoic acid, 23 g ofN-hydroxysuccineimide and 800 ml of dichloromethane was incubated on iceand stirred. To this 41.3 g of N,N'-dicyclohexylcarbodiimide dissolvedinto 200 ml of dichloromethane was added dropwise for 1 hour. After 1.5hour, 50 g ofN-methyl-N-(2-(3,4-dimethoxyphenyl)ethyl)-1,3-propanediamine was addeddropwise thereto for 30 minutes. After 5 hours the deposit was filteredand then the organic layer was washed with 0.5N aqueous hydrochloricacid. Then washing was conducted again with water and aqueous sodiumcarbonate followed by drying with magnesium sulfuric anhydride. Thesolvent was distilled off and the residue was purified by means ofsilica gel column chromatography (solvent; chloroform: methanol=50:1-3)to obtain 70.36 g (yield: 88%) of marked compound.

NMR(CDCl₃) δ; 1.5˜1.9(2H,m), 2.28(3H,s), 2.4˜2.8(6H,m), 3.04(2H,d,J=7Hz), 3.2˜3.5(2H,m), 3.84(3H,s), 3.86(3H,s), 5.90 (2H,s), 6.00(1H,dt,J=7Hz, 18 Hz), 6.40 (1H,d,J=18 Hz), 6.6˜7.0(6H,m), 7.2(1H,br)

Working Example 97(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)##STR242##

Into 150 ml of methanol was dissolved 72 g of the(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-4-(3,4-(methylenedioxy)phenyl-3-buteneamideas obtained in the working example 93 hereabove. To this was added ethylacetate-hydrogen chloride and then ethyl acetate. These were incubatedon ice and crystallized. The crystals were filtered and thenrecrystallized with ethanol-ethyl acetate to obtain 44 g of the markedcompound (yield: 52%) as light yellow crystals.

    ______________________________________                                        Value of Elemental Analysis: as C.sub.25 H.sub.34 Cl.sub.2 N.sub.2            O.sub.2                                                                                    C         H      N                                               ______________________________________                                        Theoretical Value (%)                                                                        58.48       6.67   5.46                                        Observed Value (%)                                                                           58.27       6.51   5.37                                        ______________________________________                                    

Working Example 98(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-3-(4-dimethylamino)phenyl)propeneamide##STR243##

Into a mixture composed of 765 mg of(E)-3-(((4-(dimethylamino)phenyl))-propylenic acid, 0.67 ml oftriethylamine and 20 ml of tetrahydrofuran was added 0.64 ml ofdiethylchlorophosphate under incubation on ice and stirred for 1 hour.To this 1.0 g ofN-methyl-N-(((2-(3,4-dimethoxyphenyl)ethyl)))-1,3-propanediamine wasadded under incubation on ice and stirred for 2 hours. Water was addedinto reactive liquid, extraction was conducted with dichloromethane anddried up with magnesium sulfuric anhydride. The solvent was distilledoff and the residue was purified by means of silica gel columnchromatography (solvent; dichloromethane : ethanol=9:1 to obtain 800 mg(yield: 47%) of the marked compound as yellow oily matter.

NMR(CDCl₃) δ; 1.56˜1.9(2H,m), 2.74(3H,s), 2.3˜2.9(6H,m), 3.00(6H,s),3.3˜3.7(2H,m), 3.84(3H,s), 3.88(3H,s), 6.06(1H,d,J=16 Hz),6.5˜7.0(6H,m), 7.2˜7.7(4H,m)

Working Example 99(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-(3-(4-hydroxyphenyl)propeneamide##STR244##

A mixture composed of 0.82 g of (E)-3-(4-hydroxyphenyl)-propylenic acid,1.68 ml of triethylamine and 5 ml of acetnitrile was cooled down to -10°C. and then stirred. To this was added dropwise 0.92 ml ofethylchloroformate and stirred for 30 minutes. Then was added dropwisethereto 3 ml of acetnitrile solution of 3.02 g ofN-methyl-N-(2-(3,4-dimethoxyphenyl)ethyl)-1,3-propanediamine and thesewere reacted at room temperature for 1 hour. Water was added thereto,extraction was conducted with chloroform and dried up with magnesiumsulfuric anhydride. The solvent was distilled off and the residue waspurified by means of silica gel column chromatography (solvent;chloroform : methanol=10:1) to obtain 0.59 g (yield: 30%) of the markedcompound as yellow amorphous matter.

NMR(DMSO-d₆) δ; 1.4˜1.8(2H,m), 2.20(3H,s), 2.3˜2.8(6H,m), 3.0˜3.3(2H,m),3.86(3H,s), 3.88(3H,s), 6.30(1H,d,J=16 Hz), 6.6˜6.8(5H,m),7.1˜7.5(3H,m), 7.85(1H,br)

Working Example 100(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-3-(3,4-(methylenedioxy)benzilidene-2-pyrrolidinone##STR245##

A mixture composed of 1.17 g of(E)-N-(3-chloropropyl)-3-(3,4-(methylenedioxy)benzilidene)-2-pyrrolidinone,1.55 g of N-methyl-2-(3,4-dimethoxyphenyl)ethyl)amine hydroiodic acid,1.33 g of potassium carbonate anhydride and 8 ml ofN,N'-dimethylformamide was stirred at 90° C. for 5 hours. These werecooled down, water was added thereto, extraction was conducted withchloroform and then dried up with sodium sulfuric anhydride. The solventwas distilled off and the residue was purified by means of silica gelcolumn chromatography (solvent; chloroform : methanol=30:1) to obtain1.69 g (yield: 93%) of the marked compound as yellow oily matter.

NMR(CDCl₃) δ; 1.5˜2.0(2H,m), 2.2˜2.8(9H,m), 2.8˜3.1(2H,m),3.2˜3.6(4H,m), 3.83(3H,s), 3.85(3H,s), 5.94(2H,s), 6.6˜7.1(6H,m),7.1˜7.4(1H,m)

Working Example 101-107

The following compounds were obtained by the same method as in WorkingExample 100.

Working Example 101(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-3-(4-fluorobenzilidene)-2-pyrrolidinone##STR246##

Slightly yellowish oily matter

NMR(CDCl₃) δ; 1.7˜2.1(2H,m), 2.40(3H,s), 2.4˜3.0(6H,m), 3.0˜3.2(2H,m),3.4˜3.7(4H,m), 3.90(3H,s), 3.94(3H,s), 6.7˜7.0(3H,m), 7.0˜7.6(5H,m)

Working Example 102(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-3-(4-fluorobenzilidene)-2-piperidone##STR247##

Slightly yellowish oily matter

NMR(CDCl₃) δ; 1.6˜2.0(4H,m), 2.32(3H,s), 2.3˜2.8(8H,m), 3.2˜3.6(4H,m),3.82(3H,s), 3.84(3H,s), 6.6˜6.8(3H,m), 6.9˜7.4(4H,m), 7.7(1H,s)

Working Example 103(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)amino)propyl)))-3-(4-fluorobenzilidene)-2-pyrrolidinone##STR248##

White solid matter

NMR(CDCl₃) δ; 1.7˜2.0(2H,m), 2.5˜3.2(7H,m) 3.1˜3.4(4H,m), 3.84(3H,s),3.86(3H,s), 6.6˜6.9(3H,m), 6.9˜7.6(5H,m)

Working Example 104(E)-N-(((3-((N'-(6,7-dimethoxy-1,2,3,4-)-tetrahydronaphthalene-2-yl)-N'-methyl)amino)propyl)))-3-(4-fluorobenzilidene)-2-pyrrolidinone##STR249##

Slightly brownish solid matter

NMR(CDCl₃) δ; 1.5˜2.2(4H,m), 2.34(3H,s), 2.4˜3.2(10H,m), 3.3˜3.7(4H,m),3.83(6H,s), 6.56(2H,s), 6.9˜7.6(5H,m)

Working Example 105(E)-N-(((3-((N'-(indane-2-yl)-N'-methyl)amino)propyl)))-3-(-4-fluorobenzilidene)-2-pyrrolidinone##STR250##

Slightly brown solid matter

NMR(CDCl₃) δ; 1.6˜2.0(2H,m), 2.27(3H,s), 2.3˜2.6(2H,m), 2.6˜3.7(11H,m),6.8˜7.6(9H,m)

Working Example 106(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-3-(4-cyanobenzilidene)-2-pyrrolidinone##STR251##

Slightly brownish oily matter

NMR(CDCl₃) δ; 1.6˜2.0(2H,m), 2.2˜2.9(9H,m), 2.9˜3.3(2H,m),3.3˜3.7(4H,m), 3.84(3H,s), 3.86(3H,s), 6.6˜6.9(3H,m), 7.2˜7.8(5H,m)

Working Example 107 (E)-N-(((3-((N'-(2-(4-pyridyl)ethyl)N'-methyl)amino)propyl)))-3-(3,4(methylenedioxy)benzilidene)-2-pyrrolidinone ##STR252##

Yellow oily matter

NMR(CDCl₃) δ; 1.5˜1.9(2H,m), 2.2˜3.2(11H,m), 3.3˜3.6(4H,m), 5.95(2H,s),6.7˜7.3(6H,m), 8.4˜8.6(2H,m)

Working Example 108(E)-N-(((3-((N'-(2-(4-methoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-3-(4-fluorophenyl)propeneamide##STR253##

A mixture composed of 0.6 g of(E)-N-(3-chloropropyl)-3-(4-fluorophenyl)propeneamide, 0.75 g ofN-methyl-N-(2-(4-methoxyphenyl)ethyl)amine.hydrochloric acid, 0.91 g ofpotassium carbonate anhydride, tetraiodine-n-butylammonium (volume incatalyst) and 5 ml of N,N'-dimethylformamide was stirred at 80° C. for 7hours. These were cooled down, water was added thereto, and extractionwas conducted with chloroform. After drying up with sodium sulfuricanhydride, the solvent was distilled off. Then the residue was purifiedby means of silica gel column chromatography (solvent; chloroform :methanol=50:1) to obtain 0.38 g (yield: 41%) of the marked compound asyellow solid matter.

NMR(CDCl₃) δ;

1.5˜1.9(2H,m, 2.34(3H,s), 2.4˜2.9(6H,m), 3.3˜3.6(2H,m), 3.72(3H,s),6.11(1H,d,J=16 Hz), 6.7˜7.7(10H,m)

Working Example 109-120

The following compounds were obtained by the same method as in WorkingExample 108 above.

Working Example 109(E)-N-(((3-((N'-(2-(4-methoxyphenyl)ethyl)-N'-aryl)amino)propyl)))-3-(4-fluorophenyl)propeneamide##STR254##

Yellow oily matter

NMR(CDCl₃) δ; 1.5˜1.9(2H,m), 2.5˜2.8(6H,m), 3.10 (2H,d,J=7 Hz),3.2˜3.5(2H,m), 3.62 (3H,s), 5.0˜5.3(2H,m), 5.5˜6.1(2H,m), 6.6˜7.6(10H,m)

Working Example 110(E)-N-(((3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-aryl)amino)propyl)))-3-(4-fluorophenyl)propeneamide##STR255##

Yellow oily matter

NMR(CDCl₃) δ; 1.5˜1.9(2H,m), 2.5˜2.9(6H,m), 3.14 (2H,d,J=7 Hz),3.3˜3.6(2H,m), 3.76 (3H,s), 3.84(3H,s), 5.0˜5.4(2H,m), 5.6˜6.0(1H,m),6.10(1H,d,J=16 Hz), 6.73(3H,s), 6.9˜7.6(6H,m)

Working Example 111(E)-N-(((3-((N'-(2-(3-methoxyphenyl)ethyl)-N'-methyl)amino)propyl)))-3(4-fluorophenyl)propeneamide ##STR256##

Yellow oily matter

NMR(CDCl₃) δ; 1.5˜1.9(2H,m), 2.29(3H,s), 2.4˜2.8(6H,m), 3.3˜3.5(2H,m),3.72(3H,s), 5.98(1H,d,J=16 Hz), 6.6˜7.6(10H,m)

Working Example 112(E)-N-(((3-((N'-(2-(3,4-methylenedioxy)phenyl)ethyl)-N'-methyl)amino)propyl)))-3-(4-fluorophenyl)propeneamide##STR257##

Yellow oily matter

NMR(CDCl₃) δ; 1.5˜1.9(2H,m), 2.28(3H,s), 2.4˜2.8(6H,m), 3.3˜3.6(2H,m),5.81(2H,s), 6.12(1H,d,J=16 Hz), 6.69(3H,s), 6.9˜7.7(6H,m)

Working Example 113 (E)-N-(((3-((N'-(2(3,4-(ethylenedioxy)phenyl)ethyl)-N'-methyl)amino)propyl)))-3-(4-fluorophenyl)propeneamide##STR258##

Slightly Yellowish oily matter

NMR(CDCl₃) δ; 1.5˜1.8(2H,m), 2.28(3H,s), 2.4˜2.8(6H,m), 3.1˜3.5(2H,m),4.10(4H,s), 6.00(1H,d,J=17 Hz), 6.4˜7.6(9H,m)

Working Example 114(E)-N-(((3-((N'-(3,4-dimethoxyphenyl)piperidine-1-yl)propyl)))-3-(4-fluorophenyl)propeneamide##STR259##

Blight Yellow oily matter

NMR(CDCl₃) δ; 1.6˜2.7(11H,m), 3.0˜3.3(2H,m), 3.3˜3.6(2H,m), 3.80(3H,s),3.84(3H,s), 6.28(1H,d,J=16 Hz), 6.69(3H,s), 6.8˜7.1(2H,m),7.1˜7.5(3H,m), 7.6(1H,br)

Working Example 115

(E)-N-(((3-(7,8-dimethoxy-1,2,4,5-tetrahydro-3-benzadipine-3-yl)propyl-3-(4-fluorophenyl)propeneamide##STR260##

White amorphous matter

NMR(CDCl₃) δ; 1.6˜2.0(2H,m), 2.5˜3.0(10H,m), 3.3˜3.6(2H,m), 3.83(6H,s),6.25(1H,d,J=16 Hz), 6.59(2H,s), 6.8˜7.7(6H,m)

Working Example 116 (E)-N(((3-((3-(3,4-dimethoxyphenyl)pyrrolidine-1-yl)propyl)))-3-(4-fluorophenyl)propeneamide##STR261##

Blight yellow oily matter

NMR(CDCl₃) δ; 1.7˜2.6(3H,m), 2.7˜3.7(10H,m), 3.80 (3H,s), 3.86(3H,s),6.40(1H,d,J=16 Hz), 6.7˜7.2(5H,m), 7.3˜7.6(3H,m), 7.64 (1H,br)

Working Example 117(E)-N-(((3-(3,4-dimethoxyphenyl)piperidine-1-yl)propyl-3-(4-fluorophenyl)propeneamide##STR262##

Blight yellow amorphous matter

NMR(CDCl₃) δ; 1.2˜2.2(7H,m), 2.5˜2.7(2H,m), 2.9˜3.2(2H,m),3.3˜3.6(2H,m), 3.79(6H,s), 6.27(1H,d,J=16 Hz), 6.6˜6.8(3H,m),6.8˜7.6(6H,m)

Working Example 118(E)-N-(((3-((2-(2-pyridyl)ethyl)-N'-methyl)amino)propyl)-3-(4-fluorophenyl)propeneamide##STR263##

Yellow oily matter

NMR(CDCl₃) δ; 1.5˜1.9(2H,m), 2.24(3H,s), 2.3˜3.1(6H,m), 3.2˜3.5(2H,m),6.24(1H,d,J=17 Hz), 6.9˜7.8(9H,m), 8.4˜8.6(1H,m)

Working Example 119(E)-N-(((3-(N'-(2-(3-pyridyl)ethyl)-N'-methyl)amino)propyl)))-3-(4-fluorophenyl)propeneamide##STR264##

Yellow oily matter

NMR(CDCl₃) δ; 1.5˜1.9(2H,m), 2.32(3H,s), 2.4˜2.9(6H,m), 3.3˜3.6(2H,m),6.07(1H,d,J=17 Hz), 6.7(1H,br), 6.9˜7.4(3H,m), 7.4˜7.7(4H,m),8.4˜8.6(2H,m)

Working Example 120(E)-N-(((3-((N'(2-(4-pyridyl)ethyl)-N'-methyl)amino)propyl)))-3-(4-fluorophenyl)propeneamide##STR265##

Yellow oily matter

NMR(CDCl₃) δ; 1.5˜1.9(2H,m), 2.32(3H,s), 2.4˜2.9(6H,m), 3.3˜3.6(2H,m),6.09(1H,d,J=17 Hz), 6.65(1H,br), 6.9˜7.2(4H,m), 7.3˜7.7(3H,m),8.4˜8.6(2H,m)

EXAMPLES OF THE COMPOUND III Preparation Example 14-(1,2-dihydro-2-oxo-l-pyridyl)benzaldehyde ##STR266##

4.4 g of 60% sodium hydride was suspended into 150 ml ofN,N-dimethylformamide, to which 10.78 g of 2-hydroxypyridine was addedlittle by little at a room temperature. 30 min after, 12.4 g of4-fluorobenzaldehyde was added and stirred at 120° C. for 3 hours. Thereaction solution was concentrated under a reduced pressure and icedwater was added, which was extracted with chloroform. After drying withanhydrous magnesium sulfate, the solvent was distilled off. Resultantcrystals were washed with ethyl acetate to obtain 10.3 g of theabove-captioned compound as fine gray powder (yield: 52%).

Melting point (°C.) 130-131

    ______________________________________                                        Elemental analysis value: As C.sub.12 H.sub.9 NO.sub.2                                     C         H      N                                               ______________________________________                                        Theoretical value (%)                                                                        72.35       4.55   7.03                                        Measured value (%)                                                                           72.51       4.66   7.12                                        ______________________________________                                    

NMR(CDCl₃) δ; 6.20(1H,dt,J=1.2 Hz and 7.2 Hz), 6.47(1H,dd,J=1.2 Hz and7.2 Hz), 7.1˜7.6(4H,m), 7.8˜8.0(2H,m), 10.04(1H,s)

Preparation Example 2 4-(3-methoxy-6-pyridazinyl)benzaldehyde ##STR267##

Under a nitrogen gas stream, 20 ml of a tetrahydrofuran solution of12.31 g of 4-bromobenzaldehyde dimethyl acetal was dropped understirring to a mixture of 1.14 g of magnesium, iodine (catalytic amount)and 30 ml of tetrahydrofuran, to prepare a Grignard reagent. TheGrignard reagent thus prepared was dropped under a room temperature to amixture of 7.00 g of 3-chloro-6-methoxypyridazine, 1.0 g ofbis(1,3-diphenylphosphinopropane) nickel (II) chloride and 50 ml oftetrahydrofuran. After stirring at a room temperature for 20 hours, icedwater and then 20 ml of 10% hydrochloric acid were added and stirred for30 min. Tetrahydrofuran was distilled off under a reduced pressure andthe residue was extracted with ethyl acetate. After drying withanhydrous sodium sulfate, the solvent was distilled off and the residuewas purified on silica gel column chromatography (solvent: n-hexane -ethyl acetate), to obtain 4193 g (yield: 48%) of the above-captionedcompound as pale orange solid.

Melting point (°C.): 139-141

    ______________________________________                                        Elemental analysis value: As C.sub.12 H.sub.10 N.sub.2 O.sub.5                             C         H      N                                               ______________________________________                                        Theoretical value (%)                                                                        67.28       4.71   13.08                                       Measured value (%)                                                                           67.32       4.74   13.24                                       ______________________________________                                    

NMR(CDCl₃) δ; 5.18(3H,s), 7.02(1H,d,J=9.4 Hz), 7.77(1H,d,J=9.4 Hz),7.8˜8.0(2H,m), 8.0˜8.2(2H,m), 10.07(1H,s)

The following compounds were synthesized in the same procedures as inthe Preparation Example 2 except for using 2-chloropyridazine,5-chloro-l-methyl-12-dihydro-2-oxopyridine,3-chloro-6-tert-butylpyridazine,5-chloro-2-(3,4-dimethoxyphenyl)methyl)pyridine respectively instead of3-chloro-6-methoxypyridazine.

4-(2-pyradinyl)benzaldehyde ##STR268##

Melting point (°C.): 85.0-86.0

    ______________________________________                                        Elemental analysis value: As C.sub.11 H.sub.8 N.sub.2 O                                    C         H      N                                               ______________________________________                                        Theoretical value (%)                                                                        71.73       4.38   15.21                                       Measured value (%)                                                                           71.83       4.48   15.17                                       ______________________________________                                    

NMR(CDCl₃) δ; 7.9˜8.2(4H,m), 8.41[8.7(2H,m), 9.00(1H,m), 10.00(1H,s)

4-(1-methyl-1,2-dihydro-2-oxo-5-pyridyl)benzaldehyde ##STR269##

NMR(CDCl₃) δ; 3.61(3H,s), 6.5˜6.6(2H,m), 7.5˜7.7(4H,m), 7.8˜7.9(2H,m),9.92(1H,s)

4-(2,3-dihydro-3-oxo-6-pyridazinyl)benzaldehyde ##STR270##

Melting point (°C.): 291-292

    ______________________________________                                        Elemental analysis value: As C.sub.11 H.sub.8 N.sub.2 O.sub.2                              C         H      N                                               ______________________________________                                        Theoretical value (%)                                                                        65.99       4.03   14.00                                       Meausured value (%)                                                                          66.21       4.15   14.02                                       ______________________________________                                    

NMR(CDCl₃) δ; 7.04(1H,d,J=10.1 Hz), 7.8˜8.2(5H,m), 10.06(1H,s),13.38(1H,br)

4-(1,2-dihydro-2-oxo-5-pyridyl)benzaldehyde ##STR271##

Melting point (°C.): 265-266.5

    ______________________________________                                        Elemental analysis value: C.sub.12 H.sub.9 NO.sub.2                                        C         H      N                                               ______________________________________                                        Theoretical value (%)                                                                        72.35       4.55   7.03                                        Measured value (%)                                                                           72.47       4.70   7.02                                        ______________________________________                                    

NMR(DMSO-d₆) δ; 6.4˜6.6(1H,m), 7.8˜8.1(6H,m), 10.04(1H,s), 12.0(1H,br)

Preparation Example 3 4-(2-methyl-1,3-thiazol-4-yl)benzaldehyde##STR272##

2.95 g of 4-(2-methyl-1,3-thiazol-4-yl)benznitrile was dissloved in 100ml of benzene and thereto was added dropwise a solution in toluene(1.5M) of diisobutylalminum hydride at the room temperature. Agitationwas made for 1 hour. An excess amount of sodium sulfate dihydrate wasadded to the mixture and the resultant was stirred at the roomtemperature. A filtrate liquid thereof was concentrated and purifiedwith column chromatography using silica gel and dichloromethane toobtain 1.95 g of the intended compound with a yield of 68%.

NMR(CDCl₃) δ; 2.77(3H,s) 7.47(1H,s) 7.8-8.1(4H,m) 10.00(1H,s)

Preparation Example 4 4-(1,3-thiazol-4-yl)benzaldehyde (light yellowsolid) ##STR273##

Production was made in the same was as shown in preparation example 3.

NMR(CDCl₃) δ; 7.70(1H,d,J=2 Hz) 7.8-8.2(4H,m) 8.88(1H,d,J=2Hz)10.02(1H,s)

Preparation Example 5(E)-4-(4-(1,2-dihydro-2-oxo-1-pyridyl)phenyl)-3-butenoic acid ##STR274##

3.00 g of 4-(1,2-dihydro-2-oxo-l-pyridyl)benzaldehyde and 6.15 ofβ-carboxyethyltriphenyl phosphonium chloride were suspended into 30 mlof tetrahydrofuran, cooled to -50° C. and stirred. 20 ml of atetrahydrofuran solution of 3.72 g of potassium-tert-butoxide wasdropped and the temperature was gradually raised to 0° C. After 10hours, iced water was added and the aqueous layer was washed with ether.The aqueous layer was adjusted to about pH 3 with concentratedhydrochloric acid, and deposited crystals were collected by filtrationto obtain 2.96 g of the above-captioned compound as pale brown yellowpowder (yield: 77%).

Melting point (°C.): 218.5-221.5

    ______________________________________                                        Elemental analysis value: As C.sub.15 H.sub.13 NO.sub.3                                    C         H      N                                               ______________________________________                                        Theoretical value (%)                                                                        70.58       5.13   5.49                                        Measured value (%)                                                                           70.55       5.23   5.42                                        ______________________________________                                    

NMR(DMSO-d₆) δ; 3.22(2H,d,J=5.7 Hz), 6.1˜6.4(4H,m), 7.1˜7.6(6H,m)

The following compounds were obtained by the same procedures.

(E)-4-(4-(3-methoxy-6-pyridazinyl)phenyl)-3-butenoic acid ##STR275##

Melting point (°C.): 181-183

    ______________________________________                                        Elemental analysis value: As C.sub.15 H.sub.14 N.sub.2 O.sub.3                             C         H      N                                               ______________________________________                                        Theoretical value (%)                                                                        66.65       5.22   10.37                                       Measured value (%)                                                                           66.70       5.08   10.38                                       ______________________________________                                    

NMR(DMSO-d₆) δ; 3.18(2H,d,J=5.7 Hz), 4.04(3H,s), 6.28(1H,dt,J=5.7 Hz and15.8 Hz), 6.52(1H,d,J=15.8 Hz), 7.18(1H,d,J=9.7 Hz), 7.3˜7.6(2H,m),7.8˜8.2(3H,m)

(E)-4-(4-(2-pyradinyl)phenyl-3-butenoic acid ##STR276##

Melting point (°C.): 207.0-208.5

    ______________________________________                                        Elemental analysis value: As C.sub.14 H.sub.12 NO.sub.2                                    C         H      N                                               ______________________________________                                        Theoretical value (%)                                                                        69.99       5.03   11.66                                       Measured value (%)                                                                           69.77       5.09   11.07                                       ______________________________________                                    

NMR(DMSO-d₆) δ; 3.25(2H,d,J=6.06 Hz), 6.43(1H,dt,J=6.0 Hz and 15.5 Hz),6.56(1H,d,J=15.5 Hz), 7.60(2H,d,J=8.0 Hz), 8.10(2H,d,J=8.0 Hz),8.59(1H,d,J=3.0 Hz), 8.70(1H,dd,J=1.0 Hz and 3.0 Hz), 9.25(1H,d,J=1.0Hz), 12.4(1H,br s)

(E)-4-(4-((1-methyl-1,2-dihydro-2-oxo-5-pyridyl)phenyl)-3-butenoic acid##STR277##

Melting point (°C.): 217.5-219.0 (decomp.)

    ______________________________________                                        Elemental analysis value: As C.sub.16 H.sub.15 NO.sub.3                                    C         H      N                                               ______________________________________                                        Theoretical value (%)                                                                        71.36       5.61   5.20                                        Measured value (%)                                                                           71.46       5.65   5.08                                        ______________________________________                                    

NMR(DMSO-d₆) δ; 3.21(2H,d,J=5.0 Hz), 3.51(3H,s), 6.32(1H,dt,J=5.0 Hz and16.0 Hz), 6.47(1H,d,J=9.0 Hz), 6.47(1H,d,J=16.0 Hz), 7.4˜7.6(4H,m),7.82(1H,dd,J=3.0 Hz and 9.0 Hz), 8.14(1H,d,J=3.0 Hz)

(E)-4-(4-(2-methyl-1,3-thiazol-4yl)phenyl)-3-butenic acid ##STR278##

Melting point (°C.): 170°-171° C.

    ______________________________________                                        Elemental analysis value: C.sub.14 H.sub.13 NO.sub.2 S                                 C    H           N      (S)                                          ______________________________________                                        calcd.     64.84  5.05        5.40 12.36                                      found      64.86  5.13        5.42 12.33                                      ______________________________________                                    

NMR(CDCl₃ +DMSO-d₆) δ; 2.73(3H,s) 3.19(2H,d,J=6 Hz), 6.0-6.6(2H,m)7.2-8.0(5H,m)

(E)-4-(4-1,3-thiazol-4-yl)phenyl)-3-butenic acid ##STR279##

Melting point (°C.): 190°-191° C.

    ______________________________________                                        Elemental analysis value: C.sub.13 H.sub.11 NO.sub.2 S                                 C    H           N      (S)                                          ______________________________________                                        calcd.     63.65  4.52        5.71 13.07                                      found      63.45  4.75        5.61 13.20                                      ______________________________________                                    

NMR(CDCl₃ +DMSO-d₆) δ; 3.20(2H,d,J=6 Hz) 6.1-6.7(2H,m) 7.42(2H,dt,J=1Hz, 8 Hz) 7.67(1H,d,J=2 Hz) 7.89(2H,dt,J=1 Hz, 8 Hz) 8.91(1H,d,J=2 Hz)

(E)-4-(2-(1H-imidazol-1-yl) thiophen-5-yl)-3-butenic acid ##STR280##

Melting point (°C.): 155.0-156.0

    ______________________________________                                        Elemental analysis value: As C.sub.11 H.sub.10 N.sub.2 O.sub.2 S                           C         H      N                                               ______________________________________                                        Theoretical value (%)                                                                        56.39       4.30   11.96                                       Measured value (%)                                                                           56.52       4.22   11.70                                       ______________________________________                                    

NMR(DMSO-d₆) δ; 3.16(2H,d,J=7.2 Hz), 5.96(1H,dt,J=7.2 Hz and 15.8 Hz),6.50(1H,d,J=15.8 Hz), 6.88(1H,d,J=3.6 Hz), 7.04(1H,s), 7.10(1H,d,J=3.6Hz), 7.54(1H,m), 8.04(1H,s)

(E)-4-(1H-imidazol-1-yl) thiophen-2-yl)-3-butenic acid ##STR281##

Melting point (°C.): 177.5-179.0

    ______________________________________                                        Elemental analysis value: As C.sub.11 H.sub.10 N.sub.2 O.sub.2 S                           C         H      N                                               ______________________________________                                        Theoretical value (%)                                                                        56.39       4.30   11.96                                       Measured value (%)                                                                           56.32       4.30   11.70                                       ______________________________________                                    

NMR(DMSO-d₆) δ; 3.18(2H,d,J=7.6 Hz), 6.13(1H,dt,J=7.6 Hz and 15.8 Hz),6.56(1H,d,J=15.8 Hz), 6.97(1H,s), 7.43(1H,s), 7.49(1H,s), 7.61(1H,s),8.12(1H,s)

Preparation Example 6(E)-4-(4-(2,3-dihydro-3-oxo-6-pyridazinyl)phenyl)-3-butenoic acid##STR282##

A mixture of 3.00 g of 4-(2,3-dihydro-3-oxo-6-pyridazinyl) benzaldehyde,6.12 g of β-ethoxyethyltriphneyl phosphonium chloride and 50 ml ofN,N-dimethylformamide was cooled to -50° C. and stirred. 20 ml of anN,N-dimethylformamide solution of 5.55 g of potassium tert-butoxide wasdropped and the temperature was gradually raised to 0° C. After 2 hours,the temperature was elevated to a room temperature and stirring wasconducted for further 10 hours. Iced water was added and the aqueouslayer was washed with chloroform. The aqueous layer was adjusted toabout pH 3 with hydrochloric acid and deposited solids were collected byfiltration. They were recrystallized from 50% hydrousN,N-dimethylformamide to obtain 1.51 g of the above-captioned compoundas pale orange powder (yield: 39%).

Melting point (°C.): 251-254

    ______________________________________                                        Elemental analysis value: As C.sub.14 H.sub.12 N.sub.2 O.sub.2                             C         H      N                                               ______________________________________                                        Theoretical value (%)                                                                        65.61       4.72   10.93                                       Measured value (%)                                                                           65.76       4.70   10.91                                       ______________________________________                                    

NMR(DMSO-d₆) δ; 3.23(2H,d,J=5.7 Hz), 6.37(1H,dt,J=5.7 Hz and 15.8 Hz),6.59(1H,d,J=15.8 Hz), 6.98(1H,d,J=10.1 Hz), 7.51(2H,d,J=8.4 Hz),7.83(2H,d,J=8.4 Hz), 8.03(1H,d,J=10.1 Hz), 13.15(1H,br)

The following compounds were synthesized in the same procedures.

(E)-4-(4-(1,2-dihydro-2-oxo-5-pyridyl)phenyl)-3-butenoic acid ##STR283##

Melting point (°C.): 250 (decomposed)

    ______________________________________                                        Elemental analysis value C.sub.15 H.sub.13 NO.sub.3                                    C           H      N                                                 ______________________________________                                        calcd. (%) 70.58         5.13   5.49                                          found (%)  70.67         5.21   5.29                                          ______________________________________                                    

NMR(DMSO-d₆) δ; 3.20(2H,d,J=6 Hz), 6.1-6.6(3H,m), 7.2-7.6(4H,m)7.6-7.9(2H,m), 12.0 (1H,br)

Preparation Example 7 MethylN-(3,4-dimethoxyphenylacetyl)piperidine-2-carboxylate ##STR284##

5.00 of piperidine-2-carboxylic acid was dissolved into an aqueous 80 mlsolution of saturated sodium hydrogen carbonate and stirred at a roomtemperature. 20 ml of an acetonitrile solution of 9.2 g of3,4-dimethoxyphenyl acetyl chloride was dropped and stirred for 30 min.After washing the aqueous layer with ethyl acetate, the aqueous layerwas adjusted to about pH 2 with concentrated hydrochloric acid andextracted with chloroform. Chloroform was distilled off and theresultant residue was refluxed for 6 hours with addition of 150 ml ofmethanol and 0.5 ml of concentrated sulfuric acid. After distilling offmethanol, an aqueous diluted solution of sodium hydrogen carbonate wasadded and extracted with ethyl acetate. After drying with anhydrousmagnesium sulfate, the solvent was distilled off and the residue waspurified on silica gel column chromatography (solvent: n-hexane:ethylacetate=1:1) to obtain 3.94 g of the above-captioned compound as yellowoil (yield: 32%).

NMR(CDCl₃) δ; 1.1˜1.9(5H,m), 2.0˜2.2(1H,m), 2.9˜3.3(1H,m),3.56(1H,d,J=14 Hz), 3.68(3H,s), 3.78(1H,d,J=14 Hz), 3.82(3H,s),3.84(3H,s), 4.4˜4.7(1H,m), 5.40(1H,m), 7.76(3H,s)

Preparation Example 8N-(2-(3,4-dimethoxyphenyl)ethyl)piperidine-2-methanol ##STR285##

2.33 g of lithium aluminum hydride was suspended into 50 ml oftetrahydrofuran and stirred. 3.94 g of methylN-(3,4-dimethoxyphenylacetyl)piperidine-2-carboxylate was dissolved in20 ml of tetrahydrofuran, which was dropped and, thereafter, refluxedfor 30 min. After cooling with ice and decomposing the excess reagentwith ethyl acetate, 2.3 ml of water, 2.3 ml of an aqueous 15% solutionof sodium hydroxide and 7 ml of water were added successively and,further, anhydrous magnesium sulfate was added and stirred. Insolublematters were filtered out and the filtrate was washed thoroughly withtetrahydrofuran. The filtrate was concentrated and purified on silicagel column chromatography (solvent:dichloromethane:methanol:concentrated aqueous ammonium=1000:100:2), toobtain 2.77 g of the above-captioned compound as white solid (yield:81%).

NMR(CDCl₃) δ; 1.1˜1.8(6H,m), 2.2˜3.2(8H,m), 3.44(1H,dd,J=5 Hz and 12Hz), 3.68(1H,dd,J=4 Hz and 12 Hz), 3.81(3H,s), 3.84(3H,s), 6.5˜6.8(3H,m)

Preparation Example 9N-(2-(3,4-dimethoxyphenyl)ethyl)piperidine-1-acetonitrile ##STR286##

2.77 g of N-(2-(3,4-dimethoxyphenyl)ethyl)piperidine-2-methanol wasdissolved in 30 ml of chloroform and cooled with ice. 0.87 ml of thionylchloride was dropped and stirred at a room temperature for 48 hours. Anaqueous solution of saturated sodium hydrogen carbonate was added andextracted with chloroform. After drying with anhydrous sodium sulfate,the solvent was distilled off and the residue was purified on silica gelcolumn chromatography (solvent: dichloromethane:methanol=100:1) can beobtained 2.77 g of pale yellow oil. 1.21 g of potassium cyanate,dicyclohexyl-18-crown-6 (catalytic amount) and 20 ml of acetonitrilewere added and refluxed for 24 hours. After allowing them to cool, anaqueous solution of potassium carbonate was added and extracted withethyl acetate. After washing with water and drying with anhydrous sodiumsulfate, the solvent was distilled off. The residue was purified onsilica gel column chromatography (solvent: n-hexane:ethyl acetate=2:1),to obtain 920 mg of the above-captioned compound as yellow oil (yield:34%).

NMR(CDCl₃) δ; 1.3˜1.8(6H,m), 2.3˜2.9(9H,m), 3.84(3H,s), 3.86(3H,s),6.8˜6.9(3H,m)

Preparation Example 10N-(2-(3,4-dimethoxyphenyl)ethyl)-2-(2-aminoethyl)piperidine ##STR287##

10 ml of a tetrahydrofuran solution of 920 mg ofN-(2-(3,4-dimethoxyphenyl)ethyl)piperidine-2-acetonitrile was dropped ata room temperature to a mixture of 360 mg of aluminum lithium hydrideand 10 ml of tetrahydrofuran. After stirring for 18 hours, it was cooledwith ice, to which sodium sulfate-10 hydrate was added little by littleand stirred violently for 30 min. The insoluble matters were filteredout and the filtrate was washed thoroughly with tetrahydrofuran. Thefiltrate was concentrated and purified on silica gel columnchromatography (solvent: dichloromethane:methanol:concentrated aqueousammonium=200:20:1), to obtain 650 mg of the above-captioned compound aspale yellow oil (yield: 70%)

NMR(CDCl₃) δ; 1.1˜2.0(8H,m), 2.0˜3.1(10H,m), 3.5˜3.7(1H,m), 3.84(3H,s),3.87(3H,s), 6.6˜6.9(3H,m)

Preparation Example 11(S)-N-(2-(3,4-dimethoxyphenyl)ethyl)pyrrolidine-2-methanol ##STR288##

50 ml of acetonitrile was added to 1.0 g of S-(+)-prolinole, 1.9 g of(2-(3,4-dimethoxyphenyl)ethyl)chloride and 1.64 g of anhydrous potassiumcarbonate and refluxed under heating for one day. After distilling offthe solvent under a reduced pressure, about 50 ml of methylene chloridewas added and deposited inorganic salts were filtered out. Afterdistilling off methylene chloride under a reduced pressure, the residuewas purified on silica gel column chromatography, to obtain 0.83 g ofthe above-captioned compound (yield: 32%).

NMR(CDCl₃) δ; 1.7˜2.0(4H,m), 2.3˜3.4(7H,m), 3.47(1H,dd,J=4.0 Hz and 11.0Hz), 3.66(1H,dd,J=4.0 Hz and 11.0 Hz), 3.88(3H,s), 3.91(3H,s),4.38(1H,br s), 6.7˜6.9(3 H,m)

Preparation Example 12(S)-N-(2-(3,4-dimethoxyphenyl)ethyl)pyrrolidine-2-acetonitrile##STR289##

The above-captioned compound was obtained by the same procedures asthose in Preparation Example 9 except for using(S)-N-(2-3,4-dimethoxyphenyl)ethyl)pyrrolidine-2-methanol as thestarting material.

NMR(CDCl₃) δ; 1.5˜3.1(12H,m), 3.1˜3.3(1H,m), 3.81(3H,s), 3.84(3H,s),6.6˜6.8(3H,m)

Preparation Example 13(S)-N-(2-(3,4-dimethoxyphenyl)ethyl)-2-(2-aminoethyl) pyrrolidine##STR290##

The above-captioned compound was obtained by the same procedures asthose in Preparation Example 10 except for using(S)-N-(2-3,4-dimethoxyphenyl)ethyl)pyrrolidine-2-acetonitrile as thestarting material.

NMR(CDCl₃) δ; 1.1˜3.3(16H,m), 3.5˜3.8(1H,m), 3.82(3H,s), 3.84(3H,s),6.6˜6.9(3H,m)

Preparation Example 14N-methyl-N-(2-(3,4-dimethoxyphenyl)propyl)-l,3-propane diamine##STR291##

A mixture of 1.55 g of N-methyl-N-(2-(3,4-dimethoxyphenyl)propyl)amine,1.98 g of N-(3-bromopropyl) phthalimide, 1.0 g of anhydrous potassiumcarbonate and 10 ml of acetonitrile was refluxed under heating for 6hours. They were allowed to cool and then concentrated after filteringout insoluble matters. The residue was purified on silica gel columnchromatography (solvent: chloroform:methanol=100:1), to obtain 2.71 g ofN-(3-(N'-(2-(3,4-dimethxoxyphenyl)propyl)-N'-methyl)amino)propyl)phthalimideas yellow oil. The product was dissolved in 20 ml of ethanol, to which0.4 ml of hydrazine monohydrate was added and refluxed under heating for2 hours. Deposited matters were filtered out and diluted aqueoussolution of sodium hydroxide was added, which was extracted withchloroform. After drying with anhydrous sodium sulfate, the solvent wasdistilled off and the residue was purified on silica gel columnchromatography (solvent: chloroform:methanol:concentrated aqueousammonia: 100:10:1) to obtain 1.54 g of the above-captioned compound asyellow oil (yield: 78%).

NMR(CDCl₃) δ; 1.23(3H,d,J=6.6 Hz), 1.3˜1.7(2H,m), 2.20(3H,s),2.2˜2.5(4H,m), 2.5˜3.1(3H,m), 3.84(3H,s), 3.87(3H,s), 6.5˜6.8(3H,m)

Preparation Example 15N-methyl-N-(3-(3,4-dimethoxyphenyl)propan-2-yl)-1,3-propane diamine##STR292##

The above-captioned compound was obtained in the same procedures asthose in preparation Example 13 by usingN-methyl-N-(3-(3,4-dimethoxyphenyl)propan-2-yl)amine instead ofN-methyl-N-(2-(3,4-dimethoxyphenyl)propyl)amine. Yellow oil

NMR(CDCl₃) δ;

0.92(3H,d,J=6.6 Hz), 1.3˜1.8(4H,m), 2.1˜3.1(10H,m), 3.84(3H,s), 3.86(3H,s), 6.6˜6.9(3H,m)

Preparation Example 16 N-(1-benzylpyrrolidin-3-yl)phthalimide ##STR293##

10.0 g of 3-amino-1-benzylpyrrolidine was dissolved into 10 ml ofchloromethane, to which 12.4 g of N-ethoxycarbonylphthalimide was addedand stirred at a room temperature for 10 hours. The solvent wasdistilled off, diethyl ether was added and insoluble matters werefiltered out. The filtrate was concentrated and purified on silica gelcolumn chromatography, to obtain 12.70 g of the above-captioned compound(yield: 73%)

NMR(CDCl₃) δ; 2.1˜2.3(2H,m), 2.6˜3.1(4H,m), 3.86(2H,s), 4.7˜5.1(1H,m),7.1˜7.3(5H,m), 7.6˜7.8(4H,m)

Preparation Example 17N-(1-(2-(3,4-dimethoxyphenyl)ethyl)pyrrolidin-3-yl) phthalimide##STR294##

12.70 g of N-(1-benzylpyrrolidin-3-yl)phthalimide was dissolved in 100ml of ethanol and then subjected to hydrogenating decomposition withaddition of 1.0 g of 10% palladium-carbon and 5.2 ml of concentratedhydrochloric acid at 60° C. under 1 atm. After 12 hours, the catalystwas filtered out and the solvent was distilled off to obtain 11.03 g ofN-(3-pyrrolidyl)phthalimide hydrochloride.

6.03 g of the hydrochloride was suspended into 100 ml of acetonitrile,to which 4.79 g of 2-(3,4-dimethoxyphenyl) ethyl chloride, 8.24 g ofanhydrous potassium carbonate and n-tetrabutyl ammonium iodide(catalytic amount) were added and refluxed under heating for 20 hours.After allowing them to cool, the inorganic salts were filtered out andthe solvent was distilled off. After adding ethyl acetate and washedwith water, they were dried with anhydrous magnesium sulfate. Thesolvent was concentrated and purified on silica gel chromatography toobtain 1.03 g of the above-captioned compound (total yield: 6.5%).

NMR(CDCl₃) δ; 2.1˜2.5(2H,m), 2.6˜3.2(8H,m), 3.87 (3H,s), 3.90(3H,s),4.95(1H,m), 6.80 (3H,bs), 7.6˜7.9(4H,m)

Preparation Example 183-amino-1-(2-(3,4-dimethoxyphenyl)ethyl)pyrrolidine ##STR295##

1.03 g of N-(1-(2-(3,4-dimethoxyphenyl)ethyl)pyrrolidin-3-yl)phthalimidewas dissolved in 50 ml of ethanol, to which 2 ml of hydrazinemonohydrate was added and refluxed under heating for 14 hours. Thesolvent was distilled off and an aqueous diluted solution of sodiumhydroxide was added to the residue and extracted with chloroform. Afterdrying with anhydrous magnesium sulfate, the solvent was distilled off,to obtain 0.68 g of the above-captioned compound (yield: 100%).

NMR(CDCl₃) δ; 1.4˜1.7(3H,m), 2.1˜2.9(9H,m), 3.4˜3.6(1H,m), 3.86(3H,s),3.88(3H,s), 6.7˜6.9(3H,m)

Preparation Example 19N-(3-((N'-(2-(3,5-dimethoxyphenyl)ethyl)-N'-methyl)amino)-2-hydroxypropyl)phthalimide##STR296##

1.25 g of N-(2,3-epoxypropyl)phthalimide and 1.0 g ofN-methyl-(2-(3,5-dimethoxyphenyl)ethyl)amine were dissolved in 50 ml ofethanol and stirred at 40° C. for 12 hours. After distilling off thesolvent, the residue was purified on silica gel column chromatography,to obtain 1.90 g of the above-captioned compound as yellow oil (yield:93%).

NMR (CDCl₃) δ: 2.32(3H,s), 2.46(2H,d,J=6.0 Hz), 2.6-2.8(4H,m)3.4(1H,brs), 3.8-4.1(9H,m), 6.2-6.4(3H,m) 7.6-7.9(4H,m)

Preparation Example 20N-methyl-N-(2-(3,5-dimethoxyphenyl)ethyl)-2-hydroxy-1,3-propane diamine##STR297##

UsingN-(3-((N'-(2-(3,5-dimethoxyphenyl)ethyl)-N'-methyl)amino)-2-hydroxypropyl)phthalimideas the starting material, a crude product was obtained in the sameprocedures as those in Preparation Example 18. Purification was effectedby silica gel column chromatography(solvent:dichloromethane:methanol:concentrated aqueous ammonia), toobtain the above-captioned compound.

NMR(CDCl₃) δ; 2.15(3H,br s, exchangeble with D₂ O), 2.3˜2.5(5H,m),2.5˜3.0(6H,m), 3.4˜3.7(1H,m), 3.76(6H,s), 6.32(3H,br s)

EXAMPLE 1(E)-N-(3-((N'-(2-(3,4-dimethoxyophenyl)ethyl)-N'-methyl)amino)propyl)-4-(4-(pyradinyl)phenyl)-3-buteneamide##STR298##

1.03 g of (E)-4-(4-(2-pyradinyl)phenyl)-3-butenic acid, 0.90 g ofN,N'-dicyclohexylcarbodiimide, 0.59 g of N-hydroxybenzotriazole, 1.16 gof N-2-((3,4-dimethoxyphenyl)ethyl)-N-methyl-1,3-propane diamine and amixture of 10 ml acetonitrile and 10 ml of water were stirred at 60° C.for 30 min. Deposited crystals were filtered out and the solution wasconcentrated under a reduced pressure. Purification was effected bysilica gel column chromatography, to obtain 1.03 g of theabove-captioned compound as pale yellow crystal.

Melting point (°C.): 84.5˜86.0

    ______________________________________                                        Elemental analysis value: As C.sub.28 H.sub.34 N.sub.4 O.sub.3                             C         H      N                                               ______________________________________                                        Theoretical value (%)                                                                        70.86       7.22   11.81                                       Measured value (%)                                                                           70.84       7.24   11.83                                       ______________________________________                                    

NMR(CDCl₃) δ; 1.5˜1.9(2H,m), 2.20(3H,s), 2.2˜2.7(6H,m), 3.04(2H,d,j=6.0Hz), 3.2˜3.5(2H,m), 3.80(6H,s), 6.28(1H,dt,J=6.0 Hz, and 17.0 Hz),6.40(1H,d,J=17.0 Hz), 6.5˜6.7(3H,m), 7.18(1H,br s), 7.3˜7.4(2H,m),7.8˜7.9(2H,m), 8.3˜8.5(2H,m), 8.88(1H,br s)

EXAMPLES 2-8

The following compounds were synthesized in the same procedures as thosein Example 1

Example 2 (E)-N-(3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)-4-(4-(3-methoxy-6-pyridazinyl)phenyl)-3-butenic acid##STR299##

Melting point (°C.): 116˜118

    ______________________________________                                        Elemental analysis value: As C.sub.29 H.sub.36 N.sub.4 O.sub.4                             C         H      N                                               ______________________________________                                        Theoretical value (%)                                                                        69.02       7.19   11.10                                       Measured value (%)                                                                           69.06       7.17   11.04                                       ______________________________________                                    

NMR(CDCl₃) δ; 1.5˜1.9(2H,m), 2.3˜2.8(6H,m), 3.08(2H,d,J=6.2 Hz),3.2˜3.5(2H,m), 3.82(6H,s), 4.18(3H,s), 6.22(1H,dt, J=6.2 Hz and 15.1Hz), 6.52(1H,d,J=15.1 Hz), 6.6˜6.8(3H,m), 7.02(1H,d,J=9.2 Hz),7.27(1H,br), 7.44(1H,d,J=8.4 Hz), 7.73(1H,d,J=9.2 Hz), 7.93(1H,d,J=8.4Hz)

Example 3(E)-N-(3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)-4-(4-(1,2-dihydro-2-oxo-1-pyridyl)phenyl)-3-buteneamide##STR300##

Melting point (°C.): 114-116

    ______________________________________                                        Elemental analysis value: As C.sub.29 H.sub.35 N.sub.3 O.sub.4.1/4H.sub.2                  C         H      N                                               ______________________________________                                        Theoretical value (%)                                                                        70.49       7.24   8.50                                        Measured value (%)                                                                           70.20       7.07   8.42                                        ______________________________________                                    

NMR(CDCl₃) δ; 1.5˜1.9(2H,m), 2.16(3H,s), 2.4˜2.9(6H,m), 3.06(2H,d,J=6.2Hz), 3.1˜3.5(2(H,m), 3.80(3H,s), 3.82(3H,s), 5.9˜6.8(7(H,m),6.9˜7.5(7H,m)

Example 4(E)-N-(3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)-4-(4-((1-methyl-1,2-dihydro-2-oxo-5-pyridyl)phenyl)-3-buteneamide(yellow oil) ##STR301##

NMR(CDCl₃) δ; 1.5-1.9(2H,m), 2.23(3H,s), 2.4-2.7(6H,m), 3.06(2H,d,J=6Hz), 3.2-3.5(2H,m), 3.60(3H,s), 3.82(3H,s), 3.83(3H,s) 6.26(1H,dt,J=6 Hzand 16 Hz), 6.43(1H,d,J=16 Hz), 0.5-6.8(4H,m), 7.2-7.4(5H,m),7.46(1H,d,J=3 Hz), 7.58(1H,dd,J=3 Hz, 9 Hz)

Example 5(E)-N-(3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)-4-(4-(1,2-dihydro-2-oxo-5-pyridyl)phenyl-3-buteneamide(yellow solid) ##STR302##

NMR(CDCl₃) δ; 1.5-1.8(2H,m), 2.20(2H,s), 2.4-2.8(6H,m), 3.04(2H,d,J=7Hz), 3.2-3.5(2H,m), 3.78(3H,s), 3.80(3H,s) 6.1-6.5(2H,m), 6.5-6.8(4H,m),7.2-7.8(7H,m)

Example 6(E)-N-(3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)-4-(4-(2,3-dihydro-3-oxo-6-pyridazinyl)phenyl)-3-buteneamide##STR303##

Melting point (°C.): 129-131

    ______________________________________                                        Elemental analysis value: As C.sub.28 H.sub.34 N.sub.4 O.sub.4.1/4H.sub.2                  C         H      N                                               ______________________________________                                        Theoretical value (%)                                                                        67.92       7.02   11.32                                       Measured value (%)                                                                           67.86       6.97   11.35                                       ______________________________________                                    

NMR(CDCl₃) δ; 1.5˜1.9(2H,m), 2.21(3H,s), 2.3˜2.8(6H,m), 3.07(2H,d,J=5.7Hz), 3.2˜3.5(2H,m), 3.82(3H,s), 3.83(3H,s), 6.0˜6.9(5H,m),7.03(1H,d,J=9.7 Hz), 7.2˜7.5(3H,m), 7.5˜7.8(3H,m)

Example 7(E)-N-(3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)-4-(4-(1,3-thiazol-4-yl)phenyl)-3-buteneamide (light yellow oil) ##STR304##

NMR(CDCl₃) δ; 1.4-1.9(2H,m), 2.14(3H,s), 2.3-2.7(6H,m) 3.04(2H,d,J=6Hz), 3.1-3.5(2H,m), 3.78(6H,s) 5.9-6.8(5H,m), 7.40(1H,brs),7.44(1H,d,J=2 Hz), 7.5-8.0(4H,m), 8.77(1H,d,J=2 Hz)

Example 8(E)-N-(3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)-4-(4-(2-methyl-1,3-thiazol-4-yl)phenyl)-3-buteneamide (light yellow oil) ##STR305##

NMR(CDCl₃) δ; 1.4-1.9(2H,m), 2.15(3H,s), 2.3-2.9(9H,m) 3.05(2H,d,J=6Hz), 3.1-3.5(2H,m) 3.81(6H,s), 6.1-6.8(5H,m), 7.1-8.0(6H,m)

Example 9(E)-N-(3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)anino)propyl)-4-(4-(1H-imidazol-1-yl)thiophen-2-yl)-3-buteneamide ##STR306##

Yellow oil

NMR(CDCl₃) δ; 1.5˜1.9(2H,m), 2.24(3H,s), 2.4˜2.8(6H,m), 2.97(2H,d,J=6.5Hz), 3.1˜3.5(2H,m), 3.78(3H,s), 3.81(3H,s), 6.08(1H,dt,J=6.5 Hz and 15.5Hz), 6.46(1H,d,J=15.5 Hz), 6.6˜6.8(3H,m), 6.91(2H,s), 7.0˜7.2(2H,m),7.30(1H,br), 7.68(1H,s)

Example 10 (E)-N-(3-((N'-(2-(34-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl)-4(2-(1H-imidazol-1-yl)thiophen-5-yl)-3-buteneamide ##STR307##

Yellow oil

NMR(CDCl₃) δ; 1.5˜1.9(2H,m), 2.13(3H,s), 2.4˜2.8(6H,m), 2.96(1H,d,J=6.5Hz), 3.2˜3.5(2H,m), 3.80(3H,s), 3.82(3H,s), 5.97(1H,dt,J=6.5 Hz and 15.8Hz), 6.42(1H,d,J=15.8 Hz), 6.6˜6.9(5H,m), 7.08(2H,s), 7.28(1H,br),7.64(1H,s)

Example 11(E)-N-(N'-(2-(3,4-dimethoxyphenyl)ethyl)-3-pyrrolidino)-4-(4-(1H-imidazol-1-yl)phenyl)-3-buteneamide ##STR308##

Yellow oil

NMR(CDCl₃) δ; 1.5˜1.9(1H,m), 2.1˜3.0(9H,m), 3.12(2H,d,J=6.5 Hz),3.78(3H,s), 3.80(3H,s), 6.34(1H,dt,J=6.5 Hz and 17.0 Hz),6.44(1H,d,J=17.0 Hz), 6.6˜6.8(4H,m), 7.11(1H,br s), 7.2˜7.5(5H,m),7.77(1H,br s)

Example 12(E)-N-(3-(3-(3,4-dimethoxyphenyl)-1-pyrrolidino)propyl-4-(4-(1H-imidazol-1-yl)phenyl)-3-buteneamide ##STR309##

Yellow oil

NMR(CDCl₃ -CD₃ DD) δ; 1.7˜2.0(2H,m), 2.0˜2.4(1H,m), 2.5˜3.5(12H,m),3.83(3H,s), 3.86(3H,s), 6.40(1H,dt,J=6.5 Hz and 16.2 Hz),6.48(1H,d,J=16.2 Hz), 6.7˜6.9(3H,m), 7.2˜7.5(6H,m), 7.81(1H,m)

Example 13(E)-N-(2-(N'-(2-(3,4-dimethoxyphenyl)ethyl)-2-pyrrolidino)ethyl)-4-(4-(1H-imidazol-1-yl)phenyl)-3-buteneamide ##STR310##

Yellow oil

NMR(CDCl₃) δ; 1.5˜3.5(17H,m), 3.80(3H,s), 3.82(3H,s), 6.28(1H,dt,J=6.5Hz and 16.0 Hz), 6.40(1H,d,J=16.0 Hz), 6.5˜6.8(3H,m), 7.1˜7.4(7H,m),7.75(1H,br s)

Example 14(E)-N-(2-(N'-(2-(3,4-dimethoxyphenyl)ethyl)-2-pyperidino)ethyl)-4-(4-(1H-imidazol-1-yl)phenyl)-3-buteneamide ##STR311##

Yellow oil

NMR(CDCl₃) δ; 1.2˜2.0(8H,m), 2.3˜3.6(10H,m), 3.81(3H,s), 3.84(3H,s),3.9˜4.5(1H,m), 6.24(1H,dt,J=6 Hz and 16 Hz), 6.45(1H,d,J=16 Hz),6.5˜6.8(3H,m), 7.0˜7.5(7H,m), 7.80(1H,s)

Example 15(E)-N-(3-(N'-(2-(3,4-dimethoxyphenyl)propyl)-N'-methyl)amino)propyl)-4-(4-(1H-imidazol-1-yl)phenyl)-3-buteneamide ##STR312##

Yellow oil

NMR(CDCl₃) δ; 1.20(3H,d,J=6.8 Hz), 1.4˜1.8(2H,m), 2.13(3H,s),2.3˜2.6(4H,m), 2.6˜3.0(3H,m), 3.1˜3.4(2H,m), 3.79(3H,s), 3.84(3H,s),6.13(1H,dt,J=5.8 Hz and 15.1 Hz), 6.37(1H,d,J=15.1 Hz), 6.5˜6.8(3H,m),6.90(1H,br), 7.1˜7.5(6H,m), 7.76(1H,s)

Example 16(E)-N-(3-((N'-(3-(3,4-dimethoxyphenyl)-2-propyl)-N'-methylpropyl)-4-(4-(1H-imidazol-1-yl)phenyl)-3-buteneamide ##STR313##

Yellow oil

NMR(CDCl₃) δ; 0.92(3H,d,J=6.5 Hz), 1.5˜1.9(2H,m), 2.23(3H,s),2.3˜3.1(5H,m), 3.3˜3.5(2H,m), 3.82(3H,s), 3.84(3H,s), 6.25(1H,dt,J=6.2Hz and 15.8 Hz), 6.50(1H,d,J=15.8 Hz), 6.6˜6.9(3H,m), 7.1˜7.6(7H,m),7.83(1H,s)

Example 17(E)-N-(3-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)-2-hydroxypropyl)-4-(4-(1H-imidazol-1-yl)phenyl-3-buteneamide(light yellow, viscous liquid) ##STR314##

NMR(CDCl₃) δ; 2.32(3H,s), 2.4(2H,d,J=7 Hz), 2.5˜2.8(4H,m),2.9˜3.5(4H,m), 3.16(2H,d,J=7 Hz), 3.8(3H,s), 3.84(3H,s), 6.0˜6.5(2H,m),6.5˜6.8(3H,m), 7.1˜7.5(7H,m), 7.8(1H,s).

Example 18(E)-N-(3-((N'-(2-(3.5-dimethoxyphenyl)ethyl)-N'-methyl)amino)-2-hydroxypropyl)-4-(4-(1H-imidazol-1-yl)phenyl-3-buteneamide (colorless oil) ##STR315##

NMR(CDCl₃) δ; 2.32(3H,s) 2.39(2H,d,J=7.0 Hz) 2.5-2.8(4H,m)3.0˜3.8(12H,m) 6.1-6.4(4H,m) 6.50(1H,d,J=16.0 Hz) 7.1-7.5(6H,m)7.83(1H,br s)

Example 19(E)-N-(3-(1-(2-(3,4-dimethoxyphenyl)ethyl)-3-morpholino)methyl)-4-(4-(1H-imidazol-1-yl)phenyl)-3-buteneamide##STR316##

NMR(CDCl₃) δ; 1.8-2.2(2H,m) 2.2-3.0(6H,m) 3.0-3.4(3H,m) 3.4-4.1(10H,m)6.16(1H,br s) 6.32(1H,dt,J=6.1 Hz, 15.5 Hz) 6.48(1H,d,J=15.5 Hz)6.7-6.8(3H,m) 7.14(1H,br s) 7.2-7.5(5H,m) 7.80(1H,br s)

Example 20(E)-N-(1-(2-(3,4-dimethoxyphenyl)ethyl-4-pyperidino)-4-(4-(1H-imidazol-1-yl)phenyl)-3-buteneamide##STR317##

MP 161°-161.5° C.

    ______________________________________                                        C.sub.28 H.sub.34 N.sub.4 O.sub.3                                                    C            H      N                                                  ______________________________________                                        calcd.   70.86          7.22   11.81                                          found    70.98          7.33   11.80                                          ______________________________________                                    

NMR(CDCl₃) δ; 1.1-1.7(2H,m) 1.8-2.3(4H,m) 2.4-3.0(6H,m) 3.14(2H,d,J=6.5Hz) 3.75(1H,m) 3.86(3H,s), 3.88(3H,s) 5.64(1H,br d, J=7 Hz)6.29(1H,dt,J=6.5 Hz, 15.1 Hz) 6.53(1H,d,J=15.1 Hz) 6.6-6.8(3H,m)7.1-7.6(6H,m) 7.81(1H,s)

We claim:
 1. A butenoic or propenoic acid derivative having the formula##STR318## wherein R¹ is a pyridyl group, R² and R³ each are hydrogen, alower alkyl, a cycloalkyl or an alkyl group;A is an alkylene grouphaving 1 to 6 carbon atoms wherein said alkylene may have a lower alkyl,a lower alkoxy or a hydroxy attached thereto, J is a phenyl group havingsubstituents R⁴, R⁵ and R⁶ ##STR319## wherein R⁴, R⁵ and R⁶ each are H,halogen, a lower alkyl , a lower alkoxy, a hydroxy, nitro, cyano,trifluoromethyl, an alkylsulfonyloxy, --NR⁷ R⁸ wherein R⁷ and R⁸ ishydrogen, lower alkyl or alkanoxylamino, or two of R⁴, R⁵ and R⁶ mayform an alkylenedioxy together with two adjacent carbon atoms on thephenyl ring, or R⁴, R⁵ and R⁶ may form a 5- to 7-membered carbocyclicring together with --(CH₂)--; and n is an integer of 1 to 6; or apharmaceutically acceptable salt thereof.
 2. The 4-phenyl-3-butenoicacid derivative as claimed in claim 1, in which n is an integer of 1 to3.
 3. The 4-phenyl-3-butenoic acid derivative as claimed in claim 1, inwhich R4 is a lower alkoxy, R5 is a lower alkoxy and R6 is hydrogen. 4.The 4-phenyl-3-butenoic acid derivative as claimed in claim 1, in whichJ is m,p-dimethoxyphenyl, m-dimethoxyphenyl or m,m,p-trimethoxyphenyl.5. The 4-phenyl-3-butenoic acid derivative as claimed in claim 1, whichis selected from the group consistingof:(E)-N-[3-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(3-pyridyl)phenyl)-3-butenamide, and(E)-N-[3-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(4-pyridyl)phenyl)-3-butenamide.
 6. The compound accordingto claim 1, which has the formula ##STR320## or a pharmacologicallyacceptable salt thereof.
 7. The compound according to claim 1, which hasthe formula ##STR321## or a pharmacologically acceptable salt thereof.8. A pharmacological composition which comprises a pharmacologicallyeffective amount of the butenoic or propenoic acid derivative as definedin claim 1 and a pharmacologically acceptable carrier.
 9. A method fortreating, remitting or ameliorating ischemic heart diseases byadministering the butenoic or protenoic acid derivative as defined inclaim 1 in a pharmacologically effective amount to a human being.